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| United States Patent |
5,773,451
|
|
Kohl
|
June 30, 1998
|
Substituted arylthioalkylthiopyridines
Abstract
Described are compounds of formula (I) in which R1,R2,R3,R4,R5,R6,R7,
m,n,p, and q are as defined in the description. Such compounds are
suitable for use against Helicobacter bacteria.
##STR1##
| Inventors:
|
Kohl; Bernhard (Constance, DE)
|
| Assignee:
|
BYK Gulden Lomberg Chemische Fabrik GmbH (Constance, DE)
|
| Appl. No.:
|
564285 |
| Filed:
|
December 20, 1995 |
| PCT Filed:
|
June 28, 1994
|
| PCT NO:
|
PCT/EP95/02098
|
| 371 Date:
|
December 20, 1995
|
| 102(e) Date:
|
December 20, 1995
|
| PCT PUB.NO.:
|
WO95/01351 |
| PCT PUB. Date:
|
January 12, 1995 |
Foreign Application Priority Data
| Current U.S. Class: |
514/338; 514/269; 514/274; 544/315; 544/319; 546/256; 546/268.7; 546/269.1; 546/269.7; 546/271.1; 546/271.7; 546/272.1; 546/272.4; 546/273.7 |
| Intern'l Class: |
C07D 401/12; A61K 031/04 |
| Field of Search: |
546/273.7,272.1,271.7,271.1,269.7,272.4,269.1,268.7,256
544/315,319
514/338,269,274
|
References Cited
U.S. Patent Documents
| 4560693 | Dec., 1985 | Rainer | 514/338.
|
Primary Examiner: Fan; Jane
Attorney, Agent or Firm: Jacobson, Price, Holman & Stern, PLLC
Claims
I claim:
1. A compound of formula I
##STR2##
in which R1 is hydrogen, 1-4C-alkyl or 1-4C-alkoxy,
R2 is hydrogen, 1-4C-alkyl, 1-4C-alkoxy, halogen, trifluoromethyl,
1-4C-alkoxy which is completely or predominantly substituted by fluorine,
or chlorodifluoromethoxy or 2-chloro-1,1,2-trifluoroethoxy, or, together
with R3, bonded to adjacent ring carbons, is 1-2C-alkylenedioxy which,
optionally, is completely or partly substituted by fluorine, or
chlorotrifluoroethylenedioxy,
R3 is hydrogen, 1-4C-alkoxy which is completely or predominantly
substituted by fluorine, or chlorodifluoromethoxy or
2-chloro-1,1,2-trifluoroethoxy or, together with R2, bonded to adjacent
ring carbons, is 1-2C-alkylenedioxy which, optionally, is completely or
partly substituted by fluorine, or chlorotrifluoroethylenedioxy,
R4 is hydrogen or 1-4C-alkyl,
R5 is hydrogen, 1-4C-alkyl or 1-4C-alkoxy,
R6 is a cyclic or bicyclic radical which is substituted by R8 and R9 and is
a member selected from the group consisting of benzene, furan, thiophene,
pyrrole, oxazole, isoxazole, thiazole, thiazoline, isothiazole, imidazole,
imidazoline, pyrazole, triazole, tetrazole, thiadiazole, oxadiazole,
pyridine, pyridine N-oxide, pyrimidine and benzimidazole,
R7 is hydrogen, 1-4C-alkyl or 1-4C-alkoxy,
R8 is hydrogen, 1-4C-alkyl, hydroxyl, 1-4C-alkoxy, halogen, nitro,
carboxyl, 1-4C-alkoxycarbonyl, guanidino, 1-4C-alkyl which is substituted
by R10, or --N(R11)R12,
R9 is hydrogen, 1-4C-alkyl, 1-4C-alkoxy, fluorine or trifluoromethyl,
R10 is hydroxyl, 1-4C-alkoxy, carboxyl, 1-4C-alkoxycarbonyl or --N(R11)R12,
in which
R11 is hydrogen, 1-4C-alkyl or --CO--R13 and
R12 is hydrogen or 1-4C-alkyl, or in which
R11 and R12, together and including the nitrogen atom to which they are
both bonded, are a piperidino or morpholino radical,
R13 is hydrogen, 1-4C-alkyl or 1-4C-alkoxy,
m is a number from 2 to 7,
n is the number 0 or 1,
p is the number 0 or 1 and
q is the number 0 or 1, or a salt thereof.
2. A compound of the formula I as claimed in claim 1, in which
R1 is hydrogen, 1-4C-alkyl or 1-4C-alkoxy,
R2 is hydrogen, 1-4C-alkyl, 1-4C-alkoxy, halogen, trifluoromethyl,
1-4C-alkoxy which is completely or predominantly substituted by fluorine,
or chlorodifluoromethoxy or 2-chloro-1,1,2-trifluoroethoxy, or, together
with R3, is 1-2C-alkylenedioxy which, optionally, is completely or partly
substituted by fluorine, or chlorotrifluoroethylenedioxy,
R3 is hydrogen, 1-4C-alkoxy which is completely or predominantly
substituted by fluorine, or chlorodifluoromethoxy or
2-chloro-1,1,2-trifluoroethoxy, or, together with R2, is
1-2C-alkylenedioxy which, optionally, is completely or partly substituted
by fluorine, or chlorotrifluoroethylenedioxy,
R4 is hydrogen or 1-4C-alkyl,
R5 is hydrogen, 1-4C-alkyl or 1-4C-alkoxy,
R6 is a cyclic or bicyclic radical which is substituted by R8 and R9 and is
a member selected from the group consisting of benzene, furan, thiophene,
pyrrole, oxazole, isoxazole, thiazole, thiazoline, isothiazole, imidazole,
imidazoline, pyrazole, triazole, tetrazole, thiadiazole, oxadiazole,
pyridine, pyridine N-oxide, pyrimidine and benzimidazole,
R7 is hydrogen, 1-4C-alkyl or 1-4C-alkoxy,
R8 is hydrogen, 1-4C-alkyl, hydroxyl, 1-4C-alkoxy, halogen, guanidino,
1-4C-alkyl which is substituted by R10, or --N(R11)R12,
R9 is hydrogen, 1-4C-alkyl, 1-4C-alkoxy, fluorine or trifluoromethyl,
R10 is hydroxyl, 1-4C-alkoxy, carboxyl, or --N(R11)R12, in which
R11 is hydrogen, 1-4C-alkyl or --CO--R13 and
R12 is hydrogen or 1-4C-alkyl, or in which
R11 and R12, together and including the nitrogen atom to which they are
both bonded, are a piperidino or morpholino radical,
R13 is hydrogen, 1-4C-alkyl or 1-4C-alkoxy,
m is a number from 2 to 7,
n is the number 0 or 1,
p is the number 0 or 1 and
q is the number 0 or 1, or a salt thereof.
3. A compound of the formula I as claimed in claim 1, in which R8 is nitro,
carboxyl or 1-4C-alkoxycarbonyl, and/or in which R10 is 1-4C
alkoxycarbonyl, or a salt thereof.
4. A compound of the formula I as claimed in claim 1, in which
R1 is hydrogen,
R2 is hydrogen, halogen, methoxy, difluoromethoxy or trifluoromethyl,
R3 is hydrogen,
R4 is hydrogen,
R5 is hydrogen, 1-4C-alkyl or 1-4C-alkoxy,
R6 is a cyclic radical which is substituted by R8 and R9 and is a member
selected from the group consisting of benzene, isoxazole, thiazole,
imidazole, triazole, tetrazole, thiadiazole, pyridine, pyridine N-oxide,
and pyrimidine
R7 is hydrogen or 1-4C-alkyl,
R8 is hydrogen, 1-4C-alkyl, 1-4C-alkyl which is substituted by R10, or
amino,
R9 is hydrogen or 1-4C-alkyl,
R10 is hydroxyl, carboxyl or --N(R11)R12, in which
R11 is hydrogen, 1-4C-alkyl or --CO--R13 and
R12 is hydrogen or 1-4C-alkyl, or in which
R11 and R12, together and including the nitrogen atom to which they are
both bonded, are a piperidino radical,
R13 is hydrogen, 1-4C-alkyl or 1-4C-alkoxy,
m is a number from 2 to 4,
n is the number 0 or 1,
p is the number 0 and
q is the number 0, or a salt thereof.
5. A compound of the formula I as claimed in claim 1, in which
R1 is hydrogen,
R2 is hydrogen, halogen or methoxy,
R3 is hydrogen,
R4 is hydrogen,
R5 is hydrogen, 1-4C-alkyl or 1-4C-alkoxy,
R6 is a cyclic radical which is substituted by R8 and R9 and is a member
selected from the group consisting of benzene, isoxazole, thiazole,
imidazole, triazole, tetrazole, thiadiazole, pyridine, pyridine N-oxide,
pyrimidine and benzimidazole,
R7 is hydrogen or 1-4C-alkyl,
R8 is hydrogen, 1-4C-alkyl, hydroxyl, nitro, guanidino, carboxyl,
1-4C-alkoxycarbonyl, 1-4C-alkyl which is substituted by R10, or amino,
R9 is hydrogen or 1-4C-alkyl,
R10 is hydroxyl, carboxyl, 1-4C-alkoxycarbonyl or --N(R11)R12, in which
R11 is hydrogen, 1-4C-alkyl or --CO--R13 and
R12 is hydrogen or 1-4C-alkyl, or in which
R11 and R12, together and including the nitrogen atom to which they are
both bonded, are a piperidino radical,
R13 is hydrogen, 1-4C-alkyl or 1-4C-alkoxy,
m is a number from 2 to 4,
n is the number 0 or 1,
p is the number 0 and
q is the number 0, or a salt thereof.
6. A compound of the formula I as claimed in claim 1, in which
R1 is hydrogen,
R2 is hydrogen or methoxy,
R3 is hydrogen,
R4 is hydrogen,
R5 is 1-4C-alkyl or 1-4C-alkoxy,
R6 is a cyclic radical which is substituted by R8 and R9 and is a member
selected from the group consisting of benzene, thiazole, triazole,
tetrazole, thiadiazole and pyridine,
R7 is hydrogen,
R8 is hydrogen, 1-4C-alkyl, or methyl or ethyl which is substituted by R10,
R9 is hydrogen or 1-4C-alkyl,
R10 is hydroxyl, carboxyl or --N(R11)R12, in which
R11 is 1-4C-alkyl and
R12 is 1-4C-alkyl, or in which
R11 and R12, together and including the nitrogen atom to which they are
both bonded, are a piperidino radical,
m is the number 2 or 3,
n is the number 0,
p is the number 0 and
q is the number 0, or a salt thereof.
7. A compound of the formula I as claimed in claim 1, in which
R1 is hydrogen,
R2 is hydrogen, fluorine or methoxy,
R3 is hydrogen,
R4 is hydrogen,
R5 is 1-4C-alkyl or 1-4C-alkoxy,
R6 is a cyclic radical which is substituted by R8 and R9 and is a member
selected from the group consisting of benzene, thiazole, imidazole,
triazole, tetrazole, thiadiazole, pyridine, pyrimidine and benzimidazole,
R7 is hydrogen,
R8 is hydrogen, 1-4C-alkyl, hydroxyl, nitro, guanidino, carboxyl,
1-4C-alkoxycarbonyl, or methyl or ethyl which is substituted by R10,
R9 is hydrogen or 1-4C-alkyl,
R10 is hydroxyl, carboxyl or --N(R11)R12, in which
R11 is 1-4C-alkyl and
R12 is 1-4C-alkyl, or in which
R11 and R12, together and including the nitrogen atom to which they are
both bonded, are a piperidino radical,
m is a number from 2 to 4,
n is the number 0,
p is the number 0 and
q is the number 0, or a salt thereof.
8. A compound of the formula I as claimed in claim 1, in which
R1 is hydrogen,
R2 is hydrogen,
R3 is hydrogen,
R4 is hydrogen,
R5 is 1-4C-alkyl or 1-4C-alkoxy,
R6 is a cyclic radical which is substituted by R8 and R9 and is a member
selected from the group consisting of benzene, thiazole, triazole,
tetrazole, thiadiazole and pyridine,
R7 is hydrogen,
R8 is hydrogen, methyl, or methyl or ethyl which is substituted by R10,
R9 is hydrogen,
R10 is hydroxyl, carboxyl or --N(R11)R12, in which
R11 is methyl and
R12 is methyl, or in which R11 and R12, together and including the nitrogen
atom to which they are both bonded, are a piperidino radical,
m is the number 2 or 3,
n is the number 0,
p is the number 0 and
q is the number 0, or a salt thereof.
9. A compound of the formula I as claimed in claim 1, in which
R1 is hydrogen,
R2 is hydrogen or fluorine,
R3 is hydrogen,
R4 is hydrogen,
R5 is 1-4C-alkyl or 1-4C-alkoxy,
R6 is a cyclic radical which is substituted by R8 and R9 and is a member
selected from the group consisting of benzene, thiazole, imidazole,
triazole, tetrazole, thiadiazole, pyridine, pyrimidine and benzimidazole,
R7 is hydrogen,
R8 is hydrogen, methyl, nitro, 1-4C-alkoxycarbonyl, or methyl or ethyl
which is substituted by R10,
R9 is hydrogen,
R10 is hydroxyl, carboxyl or --N(R11)R12, in which
R11 is methyl and
R12 is methyl, or in which R11 and R12, together and including the nitrogen
atom to which they are both bonded, are a piperidino radical,
m is a number from 2 to 4,
n is the number 0,
p is the number 0 and
q is the number 0, or a salt thereof.
10. A compound of the formula I as claimed in claim 1, in which
R1 is hydrogen,
R2 is hydrogen,
R3 is hydrogen,
R4 is hydrogen,
R5 is 1-4C-alkyl or 1-4C-alkoxy,
R6 is a cyclic radical which is substituted by R8 and R9 and is a member
selected from the group consisting of benzene, thiazole, imidazole,
triazole, tetrazole, thiadiazole, pyridine and pyrimidine,
R7 is hydrogen,
R8 is hydrogen, methyl, or methyl or ethyl which is substituted by R10,
R9 is hydrogen,
R10 is carboxyl or --N(R11)R12, in which
R11 is methyl and
R12 is methyl,
m is a number from 2 to 4,
n is the number 0,
p is the number 0 and
q is the number 0, or a salt thereof.
11. A compound of claim 1 wherein R2 and R3 are bonded at the 5- and
6-positions of the benzo part of the benzimidazole ring and, together, are
1-2C-alkylenedioxy which, optionally, is completely or partly substituted
by fluorine, or chlorotrifluoroethylenedioxy.
12. A compound of claim 1 wherein R2 is hydrogen, 1-4C-alkyl, 1-4C-alkoxy,
halogen, trifluoromethyl, 1-4C-alkoxy which is completely or predominately
substituted by fluorine, or chlorodifluoromethoxy or
2-chloro-1,1,2-trifluoroethoxy.
13. A process for the preparation of a compound of the formula I as claimed
in claim 1, in which R1, R2, R3, R4, R5, R6, R7, m, n, p and q have the
meanings given in claim 1, or of one of its salts, which comprises
reacting a mercaptobenzimidazole of formula II
##STR3##
in which R1, R2, R3 and R4 have the meanings given in claim 1, with a
picoline derivative III
##STR4##
in which R5, R6, R7, m, p and q have the meanings given in claim 1 and X
is a suitable leaving group.
14. A medicament composition comprising a suitable carrier and a compound
of formula I as claimed in claim 1 or a pharmacologically tolerated salt
thereof.
15. A method of treating a mammal afflicted with a condition caused by
Helicobacter bacteria which comprises administering to the mammal an
effective amount of a compound of formula I as claimed in claim 1 or one
of its pharmacologically-tolerated salts.
16. In compounding a medicament composition having an effective amount of
an active component for combating Helicobacter bacteria, the improvement
wherein the active component is a compound of formula I as claimed in
claim 1 or one of its pharmacologically-tolerated salts.
Description
FIELD OF USE OF THE INVENTION
The invention relates to compounds which are to be used in the
pharmaceutical industry as active compounds for the preparation of
medicaments.
KNOWN TECHNICAL BACKGROUND
European Patent Application 150 586 discloses 2-(pyridylmethylthio- and
-sulfinyl)benzimidazoles which can be substituted in the 4-position of the
pyridine part of the molecule by, inter alia, alkylthio or arylthio
radicals. A long-lasting inhibition of the secretion of gastric acid is
reported for the compounds described. International Patent Application
WO89/03830 states that the same compounds and other structurally similar
compounds are suitable for treatment of osteoporosis. International Patent
Application WO92/12976 describes 2-(pyridylmethylthio- and
-sulfinyl)benzimidazoles which are substituted in a particular manner and
are said to be active against Helicobacter bacteria and for which it is
furthermore disclosed that they are said to be suitable for the prevention
and treatment of a whole range of diseases of the stomach.
SUMMARY OF THE INVENTION
The invention relates to compounds of formula I (see FIG. 1A), in which
R1 is hydrogen, 1-4C-alkyl or 1-4C-alkoxy,
R2 is hydrogen, 1-4C-alkyl, 1-4C-alkoxy, halogen, trifluoromethyl,
1-4C-alkoxy which is completely or predominantly substituted by fluorine,
or chlorodifluoromethoxy or 2-chloro-1,1,2-trifluoroethoxy, or, together
with R3, is 1-2C-alkylenedioxy which, if desired, is completely or partly
substituted by fluorine, or chlorotrifluoroethylenedioxy,
R3 is hydrogen, 1-4C-alkoxy which is completely or predominantly
substituted by fluorine, or chlorodifluoromethoxy or
2-chloro-1,1,2-trifluoroethoxy or, together with R2, is 1-2C-alkylenedioxy
which, if desired, is completely or partly substituted by fluorine, or
chlorotrifluoroethylenedioxy,
R4 is hydrogen or 1-4C-alkyl,
R5 is hydrogen, 1-4C-alkyl or 1-4C-alkoxy,
R6 is a cyclic or bicyclic radical which is substituted by R8 and R9 and is
chosen from the group consisting of benzene, furan, thiophene, pyrrole,
oxazole, isoxazole, thiazole, thiazoline, isothiazole, imidazole,
imidazoline, pyrazole, triazole, tetrazole, thiadiazole, oxadiazole,
pyridine, pyridine N-oxide, pyrimidine and benzimidazole,
R7 is hydrogen, 1-4C-alkyl or 1-4C-alkoxy,
R8 is hydrogen, 1-4C-alkyl, hydroxyl, 1-4C-alkoxy, halogen, nitro,
carboxyl, 1-4C-alkoxycarbonyl, guanidino, 1-4C-alkyl which is substituted
by R10, or --N(R11)R12,
R9 is hydrogen, 1-4C-alkyl, 1-4C-alkoxy, fluorine or trifluoromethyl,
R10 is hydroxyl, 1-4C-alkoxy, carboxyl, 1-4C-alkoxycarbonyl or --N(R11)R12,
in which
R11 is hydrogen, 1-4C-alkyl or --CO--R13 and
R12 is hydrogen or 1-4C-alkyl, or in which
R11 and R12, together and including the nitrogen atom to which they are
both bonded, are a piperidino or morpholino radical,
R13 is hydrogen, 1-4C-alkyl or 1-4C-alkoxy,
m is a number from 2 to 7,
n is the number 0 or 1,
p is the number 0 or 1 and
q is the number 0 or 1, and their salts.
BRIEF DESCRIPTION OF THE DRAWINGS
FIG. 1A is the formula of final products, whereas FIG. 1B, FIG. 1C and FIG.
1D are formulae of intermediates for preparing that final product.
DETAILS
1-4C-alkyl is a straight-chain or branched alkyl radical having 1 to 4
carbon atoms. Examples which may be mentioned are the butyl, isobutyl,
sec-butyl, tert-butyl, propyl, isopropyl, ethyl and methyl radicals.
1-4C-alkoxy is a radical which contains one of the abovementioned
1-4C-alkyl radicals, in addition to the oxygen atom. Examples which may be
mentioned are the methoxy and the ethoxy radicals.
Halogen in the context of the present invention is bromine, chlorine and
fluorine.
Examples which may be mentioned of 1-4C-alkoxy which is completely or
predominantly substituted by fluorine are the 1,2,2-trifluoroethoxy, the
2,2,3,3,3-pentafluoropropoxy, the perfluoroethoxy and, in particular, the
1,1,2,2-tetrafluoroethoxy, the trifluoromethoxy, the 2,2,2-trifluoroethoxy
and the difluoromethoxy radicals.
Examples which may be mentioned of 1-2C-alkylenedioxy which, if desired, is
completely or partly substituted by fluorine are the methylenedioxy
(--O--CH.sub.2 --O--), the ethylenedioxy (--O--CH.sub.2 --CH.sub.2 --O--),
the 1,1-difluoroethylenedioxy (--O--CF.sub.2 --CH.sub.2 --O--), the
1,1,2,2-tetrafluoroethylenedioxy (--O--CF.sub.2 --CF.sub.2 --O--) and, in
particular, the difluoromethylenedioxy (O--CF.sub.2 --O--) and the
1,1,2-trifluoroethylenedioxy (--O--CF.sub.2 --CHF--O--) radicals.
If R2 and R3 together are 1-2C-alkylenedioxy which, if desired, is
completely or partly substituted by fluorine, or
chlorotrifluoroethylenedioxy, the substituents R2 and R3 are bonded to the
benzo part of the benzimidazole ring in adjacent positions--preferably to
positions 5 and 6.
The group --S(O)q-- is bonded to a carbon atom of the cyclic or bicyclic
radical R6 in question, so that examples of radicals R6 which may be
mentioned are the radicals: phenyl, 2-furyl, 3-furyl, 2-thienyl,
3-thienyl, 3-pyrrolyl, 2-oxazolyl, 4-oxazolyl, 4-isoxazolyl, 5-isoxazolyl,
2-thiazolyl, 3-isothiazolyl, 2-imidazolyl, 3-pyrazolyl, 4-pyrazolyl,
1,2,3-triazol-4-yl, 1,2,5-thiadiazol-4-yl, 1,2,4-triazol-3-yl,
tetrazol-5-yl, 1,3,4-thiadiazol-2-yl, 1,2,3-thiadiazol-4-yl,
1,3,4-oxadiazol-2-yl, 2-pyridyl, 4-pyridyl, 2-pyrimidinyl and
2-benzimidazolyl.
The substituents R8 and optionally R9 can be bonded to the cyclic or
bicyclic radicals R6 at any conceivable position. Examples of substituted
radicals R6 which may be mentioned are: 4-methylphenyl,
3-dimethylaminomethylphenyl, 3-piperidinomethylphenyl,
3-carboxymethylphenyl, 2-dimethylaminomethyl-5-methyl-3-furyl,
1-methylpyrrol-3-yl, 4,5-dimethyl-oxazol-2-yl, 3,5-dimethyl-isoxazol-4-yl,
4,5-dimethyl-thiazol-2-yl, 4-methyl-5-carboxymethyl-thiazol-2-yl,
1-methyl-imidazol-2-yl, 1-methyl-pyrazol-3-yl,
1-(2-dimethylaminoethyl)-pyrazol-3-yl, 5-methyl-1,3,4-oxadiazol-2-yl,
1-methyl-1,2,3-triazol-4-yl, 1-methyl-1,2,4-triazol-3-yl,
1-(2-dimethylaminoethyl)-1,2,3-triazol-4-yl, 1-methyl-tetrazol-5-yl,
1-(2-dimethylaminoethyl)-tetrazol-5-yl, 1-carboxymethyl-tetrazol-5-yl,
5-methyl-1,3,4-thiadiazol-2-yl, 5-trifluoromethyl-1,3,4-thiadiazol-2-yl,
1-(2-hydroxyethyl)-tetrazol-5-yl, 2-amino-1,3,4-thiadiazol-2-yl,
3-amino-1,2,4-triazol-5-yl, 4-methyl-5-trifluoromethyl-1,2,4-triazol-3-yl
and 4-amino-pyrimidin-2-yl.
Possible radicals --C.sub.m H.sub.2m which are substituted by R6-S(O).sub.q
-- are straight-chain or branched radicals. Examples which may be
mentioned are the heptyl, isoheptyl (2-methylhexyl), hexyl, isohexyl
(2-methylpentyl), neohexyl (2,2-dimethylbutyl), pentyl, isopentyl
(3-methylbutyl), neopentyl (2,2-dimethylpropyl), butyl, isobutyl,
sec-butyl, tert-butyl, propyl, isopropyl and ethyl radicals. Examples of
radicals R6-S(O).sub.q -C.sub.m H.sub.2m which may be mentioned are:
phenylthiopentyl, phenylthioethyl, phenylthiopropyl, phenylthiobutyl,
4-methyl-phenylthioethyl, 4-methyl-phenylthiopropyl,
3-dimethylaminomethyl-phenyl-thioethyl,
3-dimethyl-aminomethyl-phenylthiopropyl,
3-piperidinomethyl-phenylthioethyl, 3-piperidinomethyl-phenylthiopropyl,
3-piperidinomethyl-phenylthiobutyl, 1-methylpyrrole-3-thioethyl,
4,5-dimethyloxazole-2-thiopropyl, 3,5-dimethyl-isoxazole-5-thioethyl,
3,5-dimethyl-isoxazole-5-thiopropyl, thiazole-2-thioethyl,
thiazole-2-thiopropyl, thiazole-2-thiobutyl,
4-methyl-5-carboxymethyl-thiazole-2-thiopropyl,
1-methylimidazole-2-thioethyl, 1-methylimidazole-2-thiopropyl,
1-methylimidazole-2-thiobutyl, imidazole-2-thioethyl,
imidazole-2-thiopropyl, pyrazole-3-thiopropyl,
1-(2-dimethylaminoethyl)-pyrazole-2-thioethyl,
1,3,4-oxadiazole-2-thioethyl, 1,3,4-oxadiazole-2-thiopropyl,
1,2,3-triazole-4-thioethyl, 1,2,3-triazole-4-thiopropyl,
1,2,3-triazole-thiobutyl, 1-methyl-1,2,3-triazole-4-thioethyl,
1-methyl-1,2,3-triazole-4-thiopropyl, 1,2,4-triazole-3-thioethyl,
1,2,4-triazole-3-thiopropyl, 3-amino-1,2,4-triazole-5-thioethyl,
3-amino-1,2,4-triazole-5-thiopropyl,
4-methyl-5-trifluoromethyl-1,2,4-triazole-3-thioethyl,
4-methyl-5-trifluoromethyl-1,2,4-triazole-3-thiopropyl,
1-methyl-1,2,4-triazole-3-thioethyl, 1-methyl-1,2,4-triazole-3-thiopropyl,
1-methyl-1,2,4-triazole-3-thiobutyl, tetrazole-5-thioethyl,
tetrazole-5-thiopropyl, tetrazole-5-thiobutyl,
1-methyl-tetrazole-5-thioethyl, 1-methyl-tetrazole-5-thiopropyl,
1-methyl-tetrazole-5-thiobutyl,
1-(2-dimethylaminoethyl)-tetrazole-5-thioethyl,
1-(2-dimethylaminoethyl)-tetrazole-5-thiopropyl,
1-(2-hydroxyethyl)-tetrazole-5-thioethyl,
1-(2-hydroxyethyl)-tetrazole-5-thiopropyl, 1,3,4-thiadiazole-2-thioethyl,
1,3,4-thiadiazole-2-thiopropyl, 5-methyl-1,3,4-thiadiazole-2-thioethyl,
5-methyl-1,3,4-thiadiazole-2-thiopropyl,
5-methyl-1,3,4-thiadiazole-2-thiobutyl,
5-trifluoromethyl-1,3,4-thiadiazole-2-thioethyl,
5-trifluoromethyl-1,3,4-thiadiazole-2-thiopropyl,
1,2,3-thiadiazole-4-thioethyl, 1,2,3-thiadiazole-4-thiopropyl,
1-carboxymethyl-tetrazole-5-thioethyl,
1-carboxymethyl-tetrazole-5-thiopropyl, 2-pyridyl-thioethyl,
2-pyridyl-thiopropyl, 2-pyridyl-thiobutyl, 4-pyridyl-thioethyl,
4-pyridyl-thiopropyl, 4-pyridyl-thiobutyl, 2-pyrimidine-thioethyl,
2-pyrimidine-thiopropyl, 2-pyrimidine-thiobutyl,
4-amino-pyrimidine-2-thioethyl, 4-amino-pyrimidine-2-thiopropyl,
2-benzimidazole-thioethyl, 2-benzimidazole-thiopropyl,
4-methyl-thiazole-5-thioethyl, 4-methyl-thiazole-5-thiopropyl,
4-methyl-thiazole-5-thiobutyl,
1-methoxycarbonylmethyltetrazole-5-thioethyl,
1-methoxycarbonylmethyltetrazole-5-thiopropyl,
1-methoxycarbonylmethyltetrazole-5-thiobutyl,
5-nitroimidazole-1-thioethyl, 5-nitroimidazole-1-thiopropyl,
5-nitroimidazole-1-thiobutyl, 2-methyl-5-nitroimidazole-1-thioethyl,
2-methyl-5-nitroimidazole-1-thiopropyl and
2-methyl-5-nitroimidazole-1-thiobutyl.
Possible salts for compounds of formula I in which n is the number 0 are
all acid addition salts. The pharmacologically tolerated salts of the
inorganic and organic acids usually used in pharmaceutical formulations
may be mentioned in particular. Salts which are not pharmacologically
tolerated and which may initially be obtained as process products, for
example during preparation of the compounds according to the invention on
an industrial scale, are converted into pharmacologically tolerated salts
by processes known to the expert. Suitable such salts are water-soluble
and water-insoluble acid addition salts with acids such as, hydrochloric
acid, hydrobromic acid, phosphoric acid, nitric acid, sulfuric acid,
acetic acid, citric acid, D-gluconic acid, benzoic acid,
2-(4-hydroxybenzoyl)benzoic acid, butyric acid, sulfosalicylic acid,
maleic acid, lauric acid, malic acid, fumaric acid, succinic acid, oxalic
acid, tartaric acid, embonic acid, stearic acid, toluenesulfonic acid,
methanesulfonic acid or 3-hydroxy-2-naphthoic acid, the acids being
employed in the preparation of salts in a ratio of amounts which is
equimolar or deviates from equimolar--depending on whether the acid is
mono- or polybasic and depending on what salt is desired.
For compounds of formula I in which n is the number 1, suitable salts are
also salts with bases. Examples of basic salts which may be mentioned are
the lithium, sodium, potassium, calcium, aluminum, magnesium, titanium,
ammonium, meglumine or guanidinium salts, it again being possible for the
bases to be employed in the salt preparation in a ratio of amounts which
is equimolar or deviates from equimolar.
Compounds of formula I which are to be singled out are those in which
R1 is hydrogen,
R2 is hydrogen, halogen or methoxy,
R3 is hydrogen,
R4 is hydrogen,
R5 is hydrogen, 1-4C-alkyl or 1-4C-alkoxy,
R6 is a cyclic radical which is substituted by R8 and R9 and is chosen from
the group consisting of benzene, isoxazole, thiazole, imidazole, triazole,
tetrazole, thiadiazole, pyridine, pyridine N-oxide, pyrimidine and
benzimidazole,
R7 is hydrogen or 1-4C-alkyl,
R8 is hydrogen, 1-4C-alkyl, hydroxyl, nitro, guanidino, carboxyl,
1-4C-alkoxycarbonyl, 1-4C-alkyl which is substituted by R10, or amino,
R9 is hydrogen or 1-4C-alkyl,
R10 is hydroxyl, carboxyl, 1-4C-alkoxycarbonyl or --N(R11)R12, in which
R11 is hydrogen, 1-4C-alkyl or --CO--R13 and
R12 is hydrogen or 1-4C-alkyl, or in which
R11 and R12, together and including the nitrogen atom to which they are
both bonded, are a piperidino radical,
R13 is hydrogen, 1-4C-alkyl or 1-4C-alkoxy,
m is a number from 2 to 4,
n is the number 0 or 1,
p is the number 0 and
q is the number 0, and their salts.
Compounds of formula I which are to be singled out in particular are those
in which
R1 is hydrogen,
R2 is hydrogen, fluorine or methoxy,
R3 is hydrogen,
R4 is hydrogen,
R5 is 1-4C-alkyl or 1-4C-alkoxy,
R6 is a cyclic radical which is substituted by R8 and R9 and is chosen from
the group consisting of benzene, thiazole, imidazole, triazole, tetrazole,
thiadiazole, pyridine, pyrimidine and benzimidazole,
R7 is hydrogen,
R8 is hydrogen, 1-4C-alkyl, hydroxyl, nitro, guanidino, carboxyl,
1-4C-alkoxycarbonyl, or methyl or ethyl which is substituted by R10,
R9 is hydrogen or 1-4C-alkyl,
R10 is hydroxyl, carboxyl or --N(R11)R12, in which
R11 is 1-4C-alkyl and
R12 is 1-4C-alkyl, or in which
R11 and R12, together and including the nitrogen atom to which they are
both bonded, are a piperidino radical,
m is a number from 2 to 4,
n is the number 0,
p is the number 0 and
q is the number 0, and their salts.
Preferred compounds of formula I are those in which
R1 is hydrogen,
R2 is hydrogen or fluorine,
R3 is hydrogen,
R4 is hydrogen,
R5 is 1-4C-alkyl or 1-4C-alkoxy,
R6 is a cyclic radical which is substituted by R8 and R9 and is chosen from
the group consisting of benzene, thiazole, imidazole, triazole, tetrazole,
thiadiazole, pyridine, pyrimidine and benzimidazole,
R7 is hydrogen,
R8 is hydrogen, methyl, nitro, 1-4C-alkoxycarbonyl, or methyl or ethyl
which is substituted by R10,
R9 is hydrogen,
R10 is hydroxyl, carboxyl or --N(R11)R12, in which
R11 is methyl and
R12 is methyl, or in which
R11 and R12, together and including the nitrogen atom to which they are
both bonded, are a piperidino radical,
m is a number from 2 to 4,
n is the number 0,
p is the number 0 and
q is the number 0, and their salts.
Particularly preferred compounds of formula I are those in which
R1 is hydrogen,
R2 is hydrogen,
R3 is hydrogen,
R4 is hydrogen,
R5 is 1-4C-alkyl or 1-4C-alkoxy,
R6 is a cyclic radical which is substituted by R8 and R9 and is chosen from
the group consisting of benzene, thiazole, imidazole, triazole, tetrazole,
thiadiazole, pyridine and pyrimidine,
R7 is hydrogen,
R8 is hydrogen, methyl, or methyl or ethyl which is substituted by R10,
R9 is hydrogen,
R10 is carboxyl or --N(R11)R12, in which
R11 is methyl and
R12 is methyl,
m is a number from 2 to 4,
n is the number 0,
p is the number 0 and
q is the number 0, and their salts.
Examples of compounds according to the invention are listed in the
following Table 1, the substituent R1 being in the 5- or 6-position and
the substituent R2 being in the 6- or 5-position respectively (because of
tautomerism in the benzimidazole ring, no differentiation can be made
between positions 5 and 6 if R4=H):
TABLE 1
__________________________________________________________________________
Compounds of formula I (see FIG. 1A) with the following substituent
definitions:
R1 R2 R3
R4
R5 R6 R7
m n p q
__________________________________________________________________________
H H H H H phenyl H 2 0 0 0
H H H H H 3-dimethylaminomethylphenyl
H 2 0 0 0
H H H H H 3-piperidinomethylphenyl
H 2 0 0 0
H H H H H 2-thiazolyl H 2 0 0 0
H H H H H 3,4-dimethyl-2-thiazolyl
H 2 0 0 0
H H H H H 2-imidazolyl H 2 0 0 0
H H H H H 1-methyl-2-imidazolyl
H 2 0 0 0
H H H H H 1,2,3-triazol-4-yl
H 2 0 0 0
H H H H H 1-methyl-1,2,3-triazol-4-yl
H 2 0 0 0
H H H H H 1,2,4-triazol-3-yl
H 2 0 0 0
H H H H H 4-methyl-1,2,4-triazol-3-yl
H 2 0 0 0
H H H H H tetrazol-5-yl H 2 0 0 0
H H H H H 1-methyltetrazol-5-yl
H 2 0 0 0
H H H H H 1-(2-dimethylaminoethyl)-tetra-
H 2 0 0 0
zol-5-yl
H H H H H 1-(2-hydroxyethyl)-tetrazol-5-
H 2 0 0 0
yl
H H H H H 1,2,3-thiadiazol-4-yl
H 2 0 0 0
H H H H H 1,3,4-thiadiazol-2-yl
H 2 0 0 0
H H H H H 5-methyl-1,3,4-thiadiazol-2-yl
H 2 0 0 0
H H H H H 2-pyridinyl H 2 0 0 0
H H H H H 4-pyridinyl H 2 0 0 0
H H H H H 2-pyrimidinyl H 2 0 0 0
H H H H H 2-benzimidazolyl
H 2 0 0 0
H H H H H 2-furanyl H 2 0 0 0
H H H H H 2-thienyl H 2 0 0 0
H H H H H 5-chloro-thiophen-2-yl
H 2 0 0 0
H H H H H 5-(2-dimethylaminomethyl)-
H 2 0 0 0
furan-2-yl
H H H H H 5-methyl-furan-2-yl
H 2 0 0 0
H H H H H 2-methyl-5-nitro-1-imidazolyl
H 2 0 0 0
H H H H H 5-nitro-1-imidazolyl
H 2 0 0 0
H OCH.sub.3
H H H phenyl H 2 0 0 0
H OCH.sub.3
H H H 3-dimethylaminomethylphenyl
H 2 0 0 0
H OCH.sub.3
H H H 3-piperidinomethylphenyl
H 2 0 0 0
H OCH.sub.3
H H H 2-thiazolyl H 2 0 0 0
H OCH.sub.3
H H H 3,4-dimethyl-2-thiazolyl
H 2 0 0 0
H OCH.sub.3
H H H 2-imidazolyl H 2 0 0 0
H OCH.sub.3
H H H 1-methyl-2-imidazolyl
H 2 0 0 0
H OCH.sub.3
H H H 1,2,3-triazol-4-yl
H 2 0 0 0
H OCH.sub.3
H H H 1-methyl-1,2,3-triazol-4-yl
H 2 0 0 0
H OCH.sub.3
H H H 1,2,4-triazol-3-yl
H 2 0 0 0
H OCH.sub.3
H H H 4-methyl-1,2,4-triazol-3-yl
H 2 0 0 0
H OCH.sub.3
H H H tetrazol-5-yl H 2 0 0 0
H OCH.sub.3
H H H 1-methyltetrazol-5-yl
H 2 0 0 0
H OCH.sub.3
H H H 1-(2-dimethylaminoethyl)-tetra-
H 2 0 0 0
zol-5-yl
H OCH.sub.3
H H H 1-(2-hydroxyethyl)-tetrazol-5-
H 2 0 0 0
yl
H OCH.sub.3
H H H 1,2,3-thiadiazol-4-yl
H 2 0 0 0
H OCH.sub.3
H H H 1,3,4-thiadiazol-2-yl
H 2 0 0 0
H OCH.sub.3
H H H 5-methyl-1,3,4-thiadiazol-2-yl
H 2 0 0 0
H OCH.sub.3
H H H 2-pyridinyl H 2 0 0 0
H OCH.sub.3
H H H 4-pyridinyl H 2 0 0 0
H OCH.sub.3
H H H 2-pyrimidinyl H 2 0 0 0
H OCH.sub.3
H H H 2-benzimidazolyl
H 2 0 0 0
H OCH.sub.3
H H H 2-furanyl H 2 0 0 0
H OCH.sub.3
H H H 2-thienyl H 2 0 0 0
H OCH.sub.3
H H H 5-chloro-thiophen-2-yl
H 2 0 0 0
H OCH.sub.3
H H H 5-(2-dimethylaminomethyl)-
H 2 0 0 0
furan-2-yl
H OCH.sub.3
H H H 5-methyl-furan-2-yl
H 2 0 0 0
H OCH.sub.3
H H H 2-methyl-5-nitro-1-imidazolyl
H 2 0 0 0
H OCH.sub.3
H H H 5-nitro-1-imidazolyl
H 2 0 0 0
H H H H CH.sub.3
phenyl H 2 0 0 0
H H H H CH.sub.3
3-dimethylaminomethylphenyl
H 2 0 0 0
H H H H CH.sub.3
3-piperidinomethylphenyl
H 2 0 0 0
H H H H CH.sub.3
2-thiazolyl H 2 0 0 0
H H H H CH.sub.3
3,4-dimethyl-2-thiazolyl
H 2 0 0 0
H H H H CH.sub.3
2-imidazolyl H 2 0 0 0
H H H H CH.sub.3
1-methyl-2-imidazolyl
H 2 0 0 0
H H H H CH.sub.3
1,2,3-triazol-4-yl
H 2 0 0 0
H H H H CH.sub.3
1-methyl-1,2,3-triazol-4-yl
H 2 0 0 0
H H H H CH.sub.3
1,2,4-triazol-3-yl
H 2 0 0 0
H H H H CH.sub.3
4-methyl-1,2,4-triazol-3-yl
H 2 0 0 0
H H H H CH.sub.3
tetrazol-5-yl H 2 0 0 0
H H H H CH.sub.3
1-methyltetrazol-5-yl
H 2 0 0 0
H H H H CH.sub.3
1-(2-dimethylaminoethyl)-tetra-
H 2 0 0 0
zol-5-yl
H H H H CH.sub.3
1-(2-hydroxyethyl)-tetrazol-5-
H 2 0 0 0
yl
H H H H CH.sub.3
1,2,3-thiadiazol-4-yl
H 2 0 0 0
H H H H CH.sub.3
1,3,4-thiadiazol-2-yl
H 2 0 0 0
H H H H CH.sub.3
5-methyl-1,3,4-thiadiazol-2-yl
H 2 0 0 0
H H H H CH.sub.3
2-pyridinyl H 2 0 0 0
H H H H CH.sub.3
4-pyridinyl H 2 0 0 0
H H H H CH.sub.3
2-pyrimidinyl H 2 0 0 0
H H H H CH.sub.3
2-benzimidazolyl
H 2 0 0 0
H H H H CH.sub.3
2-furanyl H 2 0 0 0
H H H H CH.sub.3
2-thienyl H 2 0 0 0
H H H H CH.sub.3
5-chloro-thiophen-2-yl
H 2 0 0 0
H H H H CH.sub.3
5-(2-dimethylaminomethyl)-
H 2 0 0 0
furan-2-yl
H H H H CH.sub.3
5-methyl-furan-2-yl
H 2 0 0 0
H H H H CH.sub.3
2-methyl-5-nitro-1-imidazolyl
H 2 0 0 0
H H H H CH.sub.3
5-nitro-1-imidazolyl
H 2 0 0 0
H F H H CH.sub.3
phenyl H 2 0 0 0
H F H H CH.sub.3
3-dimethylaminomethylphenyl
H 2 0 0 0
H F H H CH.sub.3
3-piperidinomethylphenyl
H 2 0 0 0
H F H H CH.sub.3
2-thiazolyl H 2 0 0 0
H F H H CH.sub.3
3,4-dimethyl-2-thiazolyl
H 2 0 0 0
H F H H CH.sub.3
2-imidazolyl H 2 0 0 0
H F H H CH.sub.3
1-methyl-2-imidazolyl
H 2 0 0 0
H F H H CH.sub.3
1,2,3-triazol-4-yl
H 2 0 0 0
H F H H CH.sub.3
1-methyl-1,2,3-triazol-4-yl
H 2 0 0 0
H F H H CH.sub.3
1,2,4-triazol-3-yl
H 2 0 0 0
H F H H CH.sub.3
4-methyl-1,2,4-triazol-3-yl
H 2 0 0 0
H F H H CH.sub.3
tetrazol-5-yl H 2 0 0 0
H F H H CH.sub.3
1-methyltetrazol-5-yl
H 2 0 0 0
H F H H CH.sub.3
1-(2-dimethylaminoethyl)-tetra-
H 2 0 0 0
zol-5-yl
H F H H CH.sub.3
1-(2-hydroxyethyl)-tetrazol-5-
H 2 0 0 0
yl
H F H H CH.sub.3
1,2,3-thiadiazol-4-yl
H 2 0 0 0
H F H H CH.sub.3
1,3,4-thiadiazol-2-yl
H 2 0 0 0
H F H H CH.sub.3
5-methyl-1,3,4-thiadiazol-2-yl
H 2 0 0 0
H F H H CH.sub.3
2-pyridinyl H 2 0 0 0
H F H H CH.sub.3
4-pyridinyl H 2 0 0 0
H F H H CH.sub.3
2-pyrimidinyl H 2 0 0 0
H F H H CH.sub.3
2-benzimidazolyl
H 2 0 0 0
H F H H H 2-furanyl H 2 0 0 0
H F H H H 2-thienyl H 2 0 0 0
H F H H H 5-chloro-thiophen-2-yl
H 2 0 0 0
H F H H H 5-(2-dimethylaminomethyl)-
H 2 0 0 0
furan-2-yl
H F H H H 5-methyl-furan-2-yl
H 2 0 0 0
H F H H H 2-methyl-5-nitro-1-imidazolyl
H 2 0 0 0
H F H H H 5-nitro-1-imidazolyl
H 2 0 0 0
H H H H OCH.sub.3
phenyl H 2 0 0 0
H H H H OCH.sub.3
3-dimethylaminomethylphenyl
H 2 0 0 0
H H H H OCH.sub.3
3-piperidinomethylphenyl
H 2 0 0 0
H H H H OCH.sub.3
2-thiazolyl H 2 0 0 0
H H H H OCH.sub.3
3,4-dimethyl-2-thiazolyl
H 2 0 0 0
H H H H OCH.sub.3
2-imidazolyl H 2 0 0 0
H H H H OCH.sub.3
1-methyl-2-imidazolyl
H 2 0 0 0
H H H H OCH.sub.3
1,2,3-triazol-4-yl
H 2 0 0 0
H H H H OCH.sub.3
1-methyl-1,2,3-triazol-4-yl
H 2 0 0 0
H H H H OCH.sub.3
1,2,4-triazol-3-yl
H 2 0 0 0
H H H H OCH.sub.3
4-methyl-1,2,4-triazol-3-yl
H 2 0 0 0
H H H H OCH.sub.3
tetrazol-5-yl H 2 0 0 0
H H H H OCH.sub.3
1-methyltetrazol-5-yl
H 2 0 0 0
H H H H OCH.sub.3
1-(2-dimethylaminoethyl)-tetra-
H 2 0 0 0
zol-5-yl
H H H H OCH.sub.3
1-(2-hydroxyethyl)-tetrazol-5-
H 2 0 0 0
yl
H H H H OCH.sub.3
1,2,3-thiadiazol-4-yl
H 2 0 0 0
H H H H OCH.sub.3
1,3,4-thiadiazol-2-yl
H 2 0 0 0
H H H H OCH.sub.3
5-methyl-1,3,4-thiadiazol-2-yl
H 2 0 0 0
H H H H OCH.sub.3
2-pyridinyl H 2 0 0 0
H H H H OCH.sub.3
4-pyridinyl H 2 0 0 0
H H H H OCH.sub.3
2-pyrimidinyl H 2 0 0 0
H H H H OCH.sub.3
2-benzimidazolyl
H 2 0 0 0
H H H H OCH.sub.3
2-furanyl H 2 0 0 0
H H H H OCH.sub.3
2-thienyl H 2 0 0 0
H H H H OCH.sub.3
5-chloro-thiophen-2-yl
H 2 0 0 0
H H H H OCH.sub.3
5-(2-dimethylaminomethyl)-
H 2 0 0 0
furan-2-yl
H H H H OCH.sub.3
5-methyl-furan-2-yl
H 2 0 0 0
H H H H OCH.sub.3
2-methyl-5-nitro-1-imidazolyl
H 2 0 0 0
H H H H OCH.sub.3
5-nitro-1-imidazolyl
H 2 0 0 0
H H H H H phenyl H 3 0 0 0
H H H H H 3-dimethylaminomethylphenyl
H 3 0 0 0
H H H H H 3-piperidinomethylphenyl
H 3 0 0 0
H H H H H 2-thiazolyl H 3 0 0 0
H H H H H 3,4-dimethyl-2-thiazolyl
H 3 0 0 0
H H H H H 2-imidazolyl H 3 0 0 0
H H H H H 1-methyl-2-imidazolyl
H 3 0 0 0
H H H H H 1,2,3-triazol-4-yl
H 3 0 0 0
H H H H H 1-methyl-1,2,3-triazol-4-yl
H 3 0 0 0
H H H H H 1,2,4-triazol-3-yl
H 3 0 0 0
H H H H H 4-methyl-1,2,4-triazol-3-yl
H 3 0 0 0
H H H H H tetrazol-5-yl H 3 0 0 0
H H H H H 1-methyltetrazol-5-yl
H 3 0 0 0
H H H H H 1-(2-dimethylaminoethyl)-tetra-
H 3 0 0 0
zol-5-yl
H H H H H 1-(2-hydroxyethyl)-tetrazol-5-
H 3 0 0 0
yl
H H H H H 1,2,3-thiadiazol-4-yl
H 3 0 0 0
H H H H H 1,3,4-thiadiazol-2-yl
H 3 0 0 0
H H H H H 5-methyl-1,3,4-thiadiazol-2-yl
H 3 0 0 0
H H H H H 2-pyridinyl H 3 0 0 0
H H H H H 4-pyridinyl H 3 0 0 0
H H H H H 2-pyrimidinyl H 3 0 0 0
H H H H H 2-benzimidazolyl
H 3 0 0 0
H H H H H 2-furanyl H 3 0 0 0
H H H H H 2-thienyl H 3 0 0 0
H H H H H 5-chloro-thiophen-2-yl
H 3 0 0 0
H H H H H 5-(2-dimethylaminomethyl)-
H 3 0 0 0
furan-2-yl
H H H H H 5-methyl-furan-2-yl
H 3 0 0 0
H H H H H 2-methyl-5-nitro-1-imidazolyl
H 3 0 0 0
H H H H H 5-nitro-1-imidazolyl
H 3 0 0 0
H OCH.sub.3
H H H phenyl H 3 0 0 0
H OCH.sub.3
H H H 3-dimethylaminomethylphenyl
H 3 0 0 0
H OCH.sub.3
H H H 3-piperidinomethylphenyl
H 3 0 0 0
H OCH.sub.3
H H H 2-thiazolyl H 3 0 0 0
H OCH.sub.3
H H H 3,4-dimethyl-2-thiazolyl
H 3 0 0 0
H OCH.sub.3
H H H 2-imidazolyl H 3 0 0 0
H OCH.sub.3
H H H 1-methyl-2-imidazolyl
H 3 0 0 0
H OCH.sub.3
H H H 1,2,3-triazol-4-yl
H 3 0 0 0
H OCH.sub.3
H H H 1-methyl-1,2,3-triazol-4-yl
H 3 0 0 0
H OCH.sub.3
H H H 1,2,4-triazol-3-yl
H 3 0 0 0
H OCH.sub.3
H H H 4-methyl-1,2,4-triazol-3-yl
H 3 0 0 0
H OCH.sub.3
H H H tetrazol-5-yl H 3 0 0 0
H OCH.sub.3
H H H 1-methyltetrazol-5-yl
H 3 0 0 0
H OCH.sub.3
H H H 1-(2-dimethylaminoethyl)-tetra-
H 3 0 0 0
zol-5-yl
H OCH.sub.3
H H H 1-(2-hydroxyethyl)-tetrazol-5-
H 3 0 0 0
yl
H OCH.sub.3
H H H 1,2,3-thiadiazol-4-yl
H 3 0 0 0
H OCH.sub.3
H H H 1,3,4-thiadiazol-2-yl
H 3 0 0 0
H OCH.sub.3
H H H 5-methyl-1,3,4-thiadiazol-2-yl
H 3 0 0 0
H OCH.sub.3
H H H 2-pyridinyl H 3 0 0 0
H OCH.sub.3
H H H 4-pyridinyl H 3 0 0 0
H OCH.sub.3
H H H 2-pyrimidinyl H 3 0 0 0
H OCH.sub.3
H H H 2-benzimidazolyl
H 3 0 0 0
H OCH.sub.3
H H H 2-furanyl H 3 0 0 0
H OCH.sub.3
H H H 2-thienyl H 3 0 0 0
H OCH.sub.3
H H H 5-chloro-thiophen-2-yl
H 3 0 0 0
H OCH.sub.3
H H H 5-(2-dimethylaminomethyl)-
H 3 0 0 0
furan-2-yl
H OCH.sub.3
H H H 5-methyl-furan-2-yl-
H 3 0 0 0
H OCH.sub.3
H H H 2-methyl-5-nitro-1-imidazolyl
H 3 0 0 0
H OCH.sub.3
H H H 5-nitro-1-imidazolyl
H 3 0 0 0
H H H H CH.sub.3
phenyl H 3 0 0 0
H H H H CH.sub.3
3-dimethylaminomethylphenyl
H 3 0 0 0
H H H H CH.sub.3
3-piperidinomethylphenyl
H 3 0 0 0
H H R H CH.sub.3
2-thiazolyl H 3 0 0 0
H H H H CH.sub.3
3,4-dimethyl-2-thiazolyl
H 3 0 0 0
H H H H CH.sub.3
2-imidazolyl H 3 0 0 0
H H H H CH.sub.3
1-methyl-2-imidazolyl
H 3 0 0 0
H H H H CH.sub.3
1,2,3-triazol-4-yl
H 3 0 0 0
H H H H CH.sub.3
1-methyl-1,2,3-triazol-4-yl
H 3 0 0 0
H H H H CH.sub.3
1,2,4-triazol-3-yl
H 3 0 0 0
H H H H CH.sub.3
4-methyl-1,2,4-triazol-3-yl
H 3 0 0 0
H H H H CH.sub.3
tetrazol-5-yl H 3 0 0 0
H H H H CH.sub.3
1-methyltetrazol-5-yl
H 3 0 0 0
H H H H CH.sub.3
1-(2-dimethylaminoethyl)-tetra-
H 3 0 0 0
zol-5-yl
H H H H CH.sub.3
1-(2-hydroxyethyl)-tetrazol-5-
H 3 0 0 0
yl
H H H H CH.sub.3
1,2,3-thiadiazol-4-yl
H 3 0 0 0
H H H H CH.sub.3
1,3,4-thiadiazol-2-yl
H 3 0 0 0
H H H H CH.sub.3
5-methyl-1,3,4-thiadiazol-2-yl
H 3 0 0 0
H H H H CH.sub.3
2-pyridinyl H 3 0 0 0
H H H H CH.sub.3
4-pyridinyl H 3 0 0 0
H H H H CH.sub.3
2-pyrimidinyl H 3 0 0 0
H H H H CH.sub.3
2-benzimidazolyl
H 3 0 0 0
H H H H CH.sub.3
2-furanyl H 3 0 0 0
H H H H CH.sub.3
2-thienyl H 3 0 0 0
H H H H CH.sub.3
5-chloro-thiophen-2-yl
H 3 0 0 0
H H H H CH.sub.3
5-(2-dimethylaminomethyl)-
H 3 0 0 0
furan-2-yl
H H H H CH.sub.3
5-methyl-furan-2-yl
H 3 0 0 0
H H H H CH.sub.3
2-methyl-5-nitro-1-imidazolyl
H 3 0 0 0
H H H H CH.sub.3
5-nitro-1-imidazolyl
H 3 0 0 0
H F H H CH.sub.3
phenyl H 3 0 0 0
H F H H CH.sub.3
3-dimethylaminomethylphenyl
H 3 0 0 0
H F H H CH.sub.3
3-piperidinomethylphenyl
H 3 0 0 0
H F H H CH.sub.3
2-thiazolyl H 3 0 0 0
H F H H CH.sub.3
3,4-dimethyl-2-thiazolyl
H 3 0 0 0
H F H H CH.sub.3
2-imidazolyl H 3 0 0 0
H F H H CH.sub.3
1-methyl-2-imidazolyl
H 3 0 0 0
H F H H CH.sub.3
1,2,3-triazol-4-yl
H 3 0 0 0
H F H H CH.sub.3
1-methyl-1,2,3-triazol-4-yl
H 3 0 0 0
H F H H CH.sub.3
1,2,4-triazol-3-yl
H 3 0 0 0
H F H H CH.sub.3
4-methyl-1,2,4-triazol-3-yl
H 3 0 0 0
H F H H CH.sub.3
tetrazol-5-yl H 3 0 0 0
H F H H CH.sub.3
1-methyltetrazol-5-yl
H 3 0 0 0
H F H H CH.sub.3
1-(2-dimethylaminoethyl)-tetra-
H 3 0 0 0
zol-5-yl
H F H H CH.sub.3
1-(2-hydroxyethyl)-tetrazol-5-
H 3 0 0 0
yl
H F H H CH.sub.3
1,2,3-thiadiazol-4-yl
H 3 0 0 0
H F H H CH.sub.3
1,3,4-thiadiazol-2-yl
H 3 0 0 0
H F H H CH.sub.3
5-methyl-1,3,4-thiadiazol-2-yl
H 3 0 0 0
H F H H CH.sub.3
2-pyridinyl H 3 0 0 0
H F H H CH.sub.3
4-pyridinyl H 3 0 0 0
H F H H CH.sub.3
2-pyrimidinyl H 3 0 0 0
H F H H CH.sub.3
2-benzimidazolyl
H 3 0 0 0
H F H H H 2-furanyl H 3 0 0 0
H F H H H 2-thienyl H 3 0 0 0
H F H H H 5-chloro-thiophen-2-yl
H 3 0 0 0
H F H H H 5-(2-dimethylaminomethyl)
H 3 0 0 0
furan-2-yl
H F H H H 5-methyl-furan-2-yl
H 3 0 0 0
H F H H H 2-methyl-5-nitro-1-imidazolyl
H 3 0 0 0
H F H H H 5-nitro-1-imidazolyl
H 3 0 0 0
H H H H OCH.sub.3
phenyl H 3 0 0 0
H H H H OCH.sub.3
3-dimethylaminomethylphenyl
H 3 0 0 0
H H H H OCH.sub.3
3-piperidinomethylphenyl
H 3 0 0 0
H H H H OCH.sub.3
2-thiazolyl H 3 0 0 0
H H H H OCH.sub.3
3,4-dimethyl-2-thiazolyl
H 3 0 0 0
H H H H OCH.sub.3
2-imidazolyl H 3 0 0 0
H H H H OCH.sub.3
1-methyl-2-imidazolyl
H 3 0 0 0
H H H H OCH.sub.3
1,2,3-triazol-4-yl
H 3 0 0 0
H H H H OCH.sub.3
1-methyl-1,2,3-triazol-4-yl
H 3 0 0 0
H H H H OCH.sub.3
1,2,4-triazol-3-yl
H 3 0 0 0
H H H H OCH.sub.3
4-methyl-1,2,4-triazol-3-yl
H 3 0 0 0
H H H H OCH.sub.3
tetrazol-5-yl H 3 0 0 0
H H H H OCH.sub.3
1-methyltetrazol-5-yl
H 3 0 0 0
H H H H OCH.sub.3
1-(2-dimethylaminoethyl)-tetra-
H 3 0 0 0
zol-5-yl
H H H H OCH.sub.3
1-(2-hydroxyethyl)-tetrazol-5-
H 3 0 0 0
yl
H H H H OCH.sub.3
1,2,3-thiadiazol-4-yl
H 3 0 0 0
H H H H OCH.sub.3
1,3,4-thiadiazol-2-yl
H 3 0 0 0
H H H H OCH.sub.3
5-methyl-1,3,4-thiadiazol-2-yl
H 3 0 0 0
H H H H OCH.sub.3
2-pyridinyl H 3 0 0 0
H H H H OCH.sub.3
4-pyridinyl H 3 0 0 0
H H H H OCH.sub.3
2-pyrimidinyl H 3 0 0 0
H H H H OCH.sub.3
2-benzimidazolyl
H 3 0 0 0
H H H H OCH.sub.3
2-furanyl H 3 0 0 0
H H H H OCH.sub.3
2-thienyl H 3 0 0 0
H H H H OCH.sub.3
5-chloro-thiophen-2-yl
H 3 0 0 0
H H H H OCH.sub.3
5-(2-dimethylaminomethyl)-
H 3 0 0 0
furan-2-yl
H H H H OCH.sub.3
5-methyl-furan-2-yl
H 3 0 0 0
H H H H OCH.sub.3
2-methyl-5-nitro-1-imidazolyl
H 3 0 0 0
H H H H OCH.sub.3
5-nitro-1-imidazolyl
H 3 0 0 0
H H H H H phenyl H 4 0 0 0
H H H H H 3-dimethylaminomethylphenyl
H 4 0 0 0
H H H H H 3-piperidinomethylphenyl
H 4 0 0 0
H H H H H 2-thiazolyl H 4 0 0 0
H H H H H 3,4-dimethyl-2-thiazolyl
H 4 0 0 0
H H H H H 2-imidazolyl H 4 0 0 0
H H H H H 1-methyl-2-imidazolyl
H 4 0 0 0
H H H H H 1,2,3-triazol-4-yl
H 4 0 0 0
H H H H H 1-methyl-1,2,3-triazol-4-yl
H 4 0 0 0
H H H H H 1,2,4-triazol-3-yl
H 4 0 0 0
H H H H H 4-methyl-1,2,4-triazol-3-yl
H 4 0 0 0
H H H H H tetrazol-5-yl H 4 0 0 0
H H H H H 1-methyltetrazol-5-yl
H 4 0 0 0
H H H H H 1-(2-dimethylaminoethyl)-tetra-
H 4 0 0 0
zol-5-yl
H H H H H 1-(2-hydroxyethyl)-tetrazol-5-
H 4 0 0 0
yl
H H H H H 1,2,3-thiadiazol-4-yl
H 4 0 0 0
H H H H H 1,3,4-thiadiazol-2-yl
H 4 0 0 0
H H H H H 5-methyl-1,3,4-thiadiazol-2-yl
H 4 0 0 0
H H H H H 2-pyridinyl H 4 0 0 0
H H H H H 4-pyridinyl H 4 0 0 0
H H H H H 2-pyrimidinyl H 4 0 0 0
H H H H H 2-benzimidazolyl
H 4 0 0 0
H H H H H 2-furanyl H 4 0 0 0
H H H H H 2-thienyl H 4 0 0 0
H H H H H 5-chloro-thiophen-2-yl
H 4 0 0 0
H H H H H 5-(2-dimethylaminomethyl)-
H 4 0 0 0
furan-2-yl
H H H H H 5-methyl-furan-2-yl
H 4 0 0 0
H H H H H 2-methyl-5-nitro-1-imidazolyl
H 4 0 0 0
H H H H H 5-nitro-1-imidazolyl
H 4 0 0 0
H OCH.sub.3
H H H phenyl H 4 0 0 0
H OCH.sub.3
H H H 3-dimethylaminomethylphenyl
H 4 0 0 0
H OCH.sub.3
H H H 3-piperidinomethylphenyl
H 4 0 0 0
H OCH.sub.3
H H H 2-thiazolyl H 4 0 0 0
H OCH.sub.3
H H H 3,4-dimethyl-2-thiazolyl
H 4 0 0 0
H OCH.sub.3
H H H 2-imidazolyl H 4 0 0 0
H OCH.sub.3
H H H 1-methyl-2-imidazolyl
H 4 0 0 0
H OCH.sub.3
H H H 1,2,3-triazol-4-yl
H 4 0 0 0
H OCH.sub.3
H H H 1-methyl-1,2,3-triazol-4-yl
H 4 0 0 0
H OCH.sub.3
H H H 1,2,4-triazol-3-yl
H 4 0 0 0
H OCH.sub.3
H H H 4-methyl-1,2,4-triazol-3-yl
H 4 0 0 0
H OCH.sub.3
H H H tetrazol-5-yl H 4 0 0 0
H OCH.sub.3
H H H 1-methyltetrazol-5-yl
H 4 0 0 0
H OCH.sub.3
H H H 1-(2-dimethylaminoethyl)-tetra-
H 4 0 0 0
zol-5-yl
H OCH.sub.3
H H H 1-(2-hydroxyethyl)-tetrazol-5-
H 4 0 0 0
yl
H OCH.sub.3
H H H 1,2,3-thiadiazol-4-yl
H 4 0 0 0
H OCH.sub.3
H H H 1,3,4-thiadiazol-2-yl
H 4 0 0 0
H OCH.sub.3
H H H 5-methyl-1,3,4-thiadiazol-2-yl
H 4 0 0 0
H OCH.sub.3
H H H 2-pyridinyl H 4 0 0 0
H OCH.sub.3
H H H 4-pyridinyl H 4 0 0 0
H OCH.sub.3
H H H 2-pyrimidinyl H 4 0 0 0
H OCH.sub.3
H H H 2-benzimidazolyl
H 4 0 0 0
H OCH.sub.3
H H H 2-furanyl H 4 0 0 0
H OCH.sub.3
H H H 2-thienyl H 4 0 0 0
H OCH.sub.3
H H H 5-chloro-thiophen-2-yl
H 4 0 0 0
H OCH.sub.3
H H H 5-(2-dimethylaminomethyl)-
H 4 0 0 0
furan-2-yl
H OCH.sub.3
H H H 5-methyl-furan-2-yl
H 4 0 0 0
H OCH.sub.3
H H H 2-methyl-5-nitro-1-imidazolyl
H 4 0 0 0
H OCH.sub.3
H H H 5-nitro-1-imidazolyl
H 4 0 0 0
H H H H CH.sub.3
phenyl H 4 0 0 0
H H H H CH.sub.3
3-dimethylaminomethylphenyl
H 4 0 0 0
H H H H CH.sub.3
3-piperidinomethylphenyl
H 4 0 0 0
H H H H CH.sub.3
2-thiazolyl H 4 0 0 0
H H H H CH.sub.3
3,4-dimethyl-2-thiazolyl
H 4 0 0 0
H H H H CH.sub.3
2-imidazolyl H 4 0 0 0
H H H H CH.sub.3
1-methyl-2-imidazolyl
H 4 0 0 0
H H H H CH.sub.3
1,2,3-triazol-4-yl
H 4 0 0 0
H H H H CH.sub.3
1-methyl-1,2,3-triazol-4-yl
H 4 0 0 0
H H H H CH.sub.3
1,2,4-triazol-3-yl
H 4 0 0 0
H H H H CH.sub.3
4-methyl-1,2,4-triazol-3-yl
H 4 0 0 0
H H H H CH.sub.3
tetrazol-5-yl H 4 0 0 0
H H H H CH.sub.3
1-methyltetrazol-5-yl
H 4 0 0 0
H H H H CH.sub.3
1-(2-dimethylaminoethyl)-tetra-
H 4 0 0 0
zol-5-yl
H H H H CH.sub.3
1-(2-hydroxyethyl)-tetrazol-5
H 4 0 0 0
yl
H H H H CH.sub.3
1,2,3-thiadiazol-4-yl
H 4 0 0 0
H H H H CH.sub.3
1,3,4-thiadiazol-2-yl
H 4 0 0 0
H H H H CH.sub.3
5-methyl-1,3,4-thiadiazol-2-yl
H 4 0 0 0
H H H H CH.sub.3
2-pyridinyl H 4 0 0 0
H H H H CH.sub.3
4-pyridinyl H 4 0 0 0
H H H H CH.sub.3
2-pyrimidinyl H 4 0 0 0
H H H H CH.sub.3
2-benzimidazolyl
H 4 0 0 0
H H H H CH.sub.3
2-furanyl H 4 0 0 0
H H H H CH.sub.3
2-thienyl H 4 0 0 0
H H H H CH.sub.3
5-chloro-thiophen-2-yl
H 4 0 0 0
H H H H CH.sub.3
5-(2-dimethylaminomethyl)-
H 4 0 0 0
furan-2-yl
H H H H CH.sub.3
5-methyl-furan-2-yl
H 4 0 0 0
H H H H CH.sub.3
2-methyl-5-nitro-1-imidazolyl
H 4 0 0 0
H H H H CH.sub.3
5-nitro-1-imidazolyl
H 4 0 0 0
H F H H CH.sub.3
phenyl H 4 0 0 0
H F H H CH.sub.3
3-dimethylaminomethylphenyl
H 4 0 0 0
H F H H CH.sub.3
3-piperidinomethylphenyl
H 4 0 0 0
H F H H CH.sub.3
2-thiazolyl H 4 0 0 0
H F H H CH.sub.3
3,4-dimethyl-2-thiazolyl
H 4 0 0 0
H F H H CH.sub.3
2-imidazolyl H 4 0 0 0
H F H H CH.sub.3
1-methyl-2-imidazolyl
H 4 0 0 0
H F H H CH.sub.3
1,2,3-triazol-4-yl
H 4 0 0 0
H F H H CH.sub.3
1-methyl-1,2,3-triazol-4-yl
H 4 0 0 0
H F H H CH.sub.3
1,2,4-triazol-3-yl
H 4 0 0 0
H F H H CH.sub.3
4-methyl-1,2,4-triazol-3-yl
H 4 0 0 0
H F H H CH.sub.3
tetrazol-5-yl H 4 0 0 0
H F H H CH.sub.3
1-methyltetrazol-5-yl
H 4 0 0 0
H F H H CH.sub.3
1-(2-dimethylaminoethyl)-tetra-
H 4 0 0 0
zol-5-yl
H F H H CH.sub.3
1-(2-hydroxyethyl)-tetrazol-5-
H 4 0 0 0
yl
H F H H CH.sub.3
1,2,3-thiadiazol-4-yl
H 4 0 0 0
H F H H CH.sub.3
1,3,4-thiadiazol-2-yl
H 4 0 0 0
H F H H CH.sub.3
5-methyl-1,3,4-thiadiazol-2-yl
H 4 0 0 0
H F H H CH.sub.3
2-pyridinyl H 4 0 0 0
H F H H CH.sub.3
4-pyridinyl H 4 0 0 0
H F H H CH.sub.3
2-pyrimidinyl H 4 0 0 0
H F H H CH.sub.3
2-benzimidazolyl
H 4 0 0 0
H F H H CH.sub.3
2-furanyl H 4 0 0 0
H F H H CH.sub.3
2-thienyl H 4 0 0 0
H F H H CH.sub.3
5-chloro-thiophen-2-yl
H 4 0 0 0
H F H H CH.sub.3
5-(2-dimethylaminomethyl)-
H 4 0 0 0
furan-2-yl
H F H H CH.sub.3
5-methyl-furan-2-yl
H 4 0 0 0
H F H H CH.sub.3
2-methyl-5-nitro-1-imidazolyl
H 4 0 0 0
H F H H CH.sub.3
5-nitro-1-imidazolyl
H 4 0 0 0
H H H H OCH.sub.3
phenyl H 4 0 0 0
H H H H OCH.sub.3
3-dimethylaminomethylphenyl
H 4 0 0 0
H H H H OCH.sub.3
3-piperidinomethylphenyl
H 4 0 0 0
H H H H OCH.sub.3
2-thiazolyl H 4 0 0 0
H H H H OCH.sub.3
3,4-dimethyl-2-thiazolyl
H 4 0 0 0
H H H H OCH.sub.3
2-imidazolyl H 4 0 0 0
H H H H OCH.sub.3
1-methyl-2-imidazolyl
H 4 0 0 0
H H H H OCH.sub.3
1,2,3-triazol-4-yl
H 4 0 0 0
H H H H OCH.sub.3
1-methyl-1,2,3-triazol-4-yl
H 4 0 0 0
H H H H OCH.sub.3
1,2,4-triazol-3-yl
H 4 0 0 0
H H H H OCH.sub.3
4-methyl-1,2,4-triazol-3-yl
H 4 0 0 0
H H H H OCH.sub.3
tetrazol-5-yl H 4 0 0 0
H H H H OCH.sub.3
1-methyltetrazol-5-yl
H 4 0 0 0
H H H H OCH.sub.3
1-(2-dimethylaminoethyl)-tetra
H 4 0 0 0
zol-5-yl
H H H H OCH.sub.3
1-(2-hydroxyethyl)-tetrazol-5-
H 4 0 0 0
yl
H H H H OCH.sub.3
1,2,3-thiadiazol-4-yl
H 4 0 0 0
H H H H OCH.sub.3
1,3,4-thiadiazol-2-yl
H 4 0 0 0
H H H H OCH.sub.3
5-methyl-1,3,4-thiadiazol-2-yl
H 4 0 0 0
H H H H OCH.sub.3
2-pyridinyl H 4 0 0 0
H H H H OCH.sub.3
4-pyridinyl H 4 0 0 0
H H H H OCH.sub.3
2-pyrimidinyl H 4 0 0 0
H H H H OCH.sub.3
2-benzimidazolyl
H 4 0 0 0
H H H H OCH.sub.3
2-furanyl H 4 0 0 0
H H H H OCH.sub.3
2-thienyl H 4 0 0 0
H H H H OCH.sub.3
5-chloro-thiophen-2-yl
H 4 0 0 0
H H H H OCH.sub.3
5-(2-dimethylaminomethyl)-
H 4 0 0 0
furan-2-yl
H H H H OCH.sub.3
5-methyl-furan-2-yl
H 4 0 0 0
H H H H OCH.sub.3
2-methyl-5-nitro-1-imidazolyl
H 4 0 0 0
H H H H OCH.sub.3
5-nitro-1-imidazolyl
H 4 0 0 0
__________________________________________________________________________
and the salts of these compounds in the tables.
The invention furthermore relates to a process for the preparation of the
compounds of formula I in which R1, R2, R3, R4, R5, R6, R7, m, n, p and q
have the abovementioned meanings, and their salts.
The process comprises
a) reacting mercaptobenzimidazoles of formula II (see FIG. 1B), in which
R1, R2, R3 and R4 have the abovementioned meanings, with picoline
derivatives III (see FIG. 1C), in which R5, R6, R7, m, p and q have the
abovementioned meanings and X is a suitable leaving group, or
b) reacting compounds of formula IV (see FIG. 1D), in which R1, R2, R3, R4,
R5, R7 and m have the abovementioned meanings, n and p are the number 0
and Y is a suitable leaving group, with thiols R6-SH, and
(if compounds of formula I where n=1 or p=1 and/or q=1 are the desired end
products), subsequently oxidizing the compounds obtained according to a)
or b) where n=0 and/or p=0 and/or q=0, and/or if desired subsequently
converting compounds obtained into the salts, and/or if desired
subsequently converting salts obtained into the free compounds.
The starting compounds can be employed as such or, where appropriate, in
the form of their salts in the abovementioned reaction.
Examples which may be mentioned of suitable leaving groups X and Y are
halogen atoms, in particular chlorine, or hydroxyl groups activated by
esterification (for example with p-toluenesulfonic acid).
The reaction of II with III is carried out in suitable, preferably polar
protic or aprotic solvents (such as methanol, ethanol, isopropanol,
dimethyl sulfoxide, acetone, dimethylformamide or acetonitrile), with the
addition of or exclusion of water. It is carried out, for example, in the
presence of a proton acceptor. Suitable proton acceptors are alkali metal
hydroxides, such as sodium hydroxide, alkali metal carbonates, such as
potassium carbonate, or tertiary amines, such as pyridine, triethylamine
or ethyldiisopropylamine. Alternatively, the reaction can also be carried
out without a proton acceptor, in which case, where appropriate--depending
on the nature of the starting compounds--the acid addition salts can
initially be separated off in a particularly pure form. The reaction
temperature can be between 0.degree. and 150.degree. C., temperatures
between 20.degree. and 80.degree. C. being preferred in the presence of
proton acceptors and temperatures between 60.degree. and 120.degree.
C.--in particular the boiling point of the solvents used--being preferred
without proton acceptors. The reaction times are between 0.5 and 30 hours.
The reaction of compounds IV with thiols R6-SH is carried out in a similar
manner to the reaction of compounds II with compounds III.
The oxidation of the sulfides (compounds of formula I where n=0) to give
the sulfoxides (compounds of formula I where n=1) is carried out under the
conditions which are familiar to the expert for the oxidation of sulfides
to sulfoxides in this context, cf., for example, J. Drabowicz and M.
Mikolajczyk, Organic Preparations and Procedures Int. 14(1-2), 45-89(1982)
or E. Block in S. Patai, The Chemistry of Functional Groups, Supplement E.
Part 1, pages 539-608, John Wiley and Sons (Interscience Publication),
1980!. Possible oxidizing agents are all the reagents usually used for the
oxidation of sulfides to sulfoxides, in particular peroxy acids, such as,
peroxyacetic acid, trifluoroperoxyacetic acid, 3,5-dinitroperoxybenzoic
acid, peroxymaleic acid, magnesium monoperoxyphthalate or, preferably,
m-chloroperoxybenzoic acid.
The reaction temperature is between -70.degree. C. and the boiling point of
the solvent used (depending on the reactivity of the oxidizing agent and
the degree of dilution), but preferably between -30.degree. and
+20.degree. C. Oxidation with halogens or with hypohalites (for example
with aqueous sodium hypochlorite solution), which is expediently carried
out at temperatures between 0.degree. and 50.degree. C., has also proved
advantageous. The reaction is expediently carried out in inert solvents,
for example aromatic or chlorinated hydrocarbons, such as benzene,
toluene, methylene chloride or chloroform, but preferably in esters or
ethers, such as ethyl acetate, isopropyl acetate or dioxane, or in
alcohols, preferably isopropanol.
The sulfoxides according to the invention are optically active compounds.
Further chirality centers may also be present in the molecule, depending
on the nature of the substituents. The invention therefore relates both to
the enantiomers and diastereomers and to their mixtures and racemates. The
enantiomers can be separated in a manner known per se (for example by the
preparation and separation of corresponding diastereomeric compounds; cf.
for example, WO92/08716).
Compounds II are known, for example, from WO86/02646, EP 134 400 or EP 127
763. Compounds III where p=0 and/or q=0 can be prepared, for example, as
described in the following examples.
For compounds III where p=1 and/or q=1, the corresponding
2-hydroxymethyl-4-mercapto-substituted pyridines are oxidized, for
example, with m-chloroperoxybenzoic acid to give the sulfoxides, and these
are then chlorinated, for example with thionyl chloride. Reaction with
2-mercaptobenzimidazoles gives compounds of formula I where p=1 and q=1.
Depending on the nature of the substituent R6, the sulfoxides where q=1 are
also obtained during oxidation to the sulfoxides where n=1. Otherwise, the
respective sulfides or sulfoxides can be prepared by choosing suitable
starting compounds or by using selective oxidizing agents.
The thiols R6-C.sub.m H.sub.2m -SH required for the preparation of III can
be prepared, for example, from the corresponding halogen compounds
analogously to J. Med. Chem. 14 (1971) 349.
The following examples illustrate the invention in more detail without
limiting it. The compounds according to the invention and the starting
compounds can be prepared in a manner analogous to that described in the
examples.
EXAMPLES
End Products
1.
2-{3-Methyl-4-(3-(5-methyl-1,3,4-thiadiazol-2-yl-thio}-propylthio)-2-pyr
idinyl!methyl!thiol-1H-benzimidazole
2-{4-(3-Chloropropylthio)-3-methyl-2-pyridinyl!-methyl!thio}-1H-benzimida
zole (0.36 g, 1.0 mmol) is added to a solution of
5-methyl-1,3,4-thiadiazole-2-thiol (0.16 g, 1.2 mmol) in 10 ml of ethanol
and 1.4 ml of 1N sodium hydroxide solution and the mixture is heated at
the boiling point under reflux for 20-30 hours. 12 ml of H.sub.2 O are
added dropwise, the mixture is allowed to cool, and the solid which has
precipitated out is filtered off, washed with water and dried in vacuo at
50.degree. C. 0.38 g (83% of theory) of the title compound is obtained as
a colorless solid of melting point 76.degree.-77.degree. C.
2.
2-{3-Methyl-4-(3-(4-methyl-1,2,4-triazol-3-yl-thio)-propylthio)-2-pyridi
nyl!methyl!thio}-1H-benzimidazole
By the procedure described in Example 1, the crude title compound
(containing water) is obtained by reaction of
4-methyl-1,2,4-triazole-3-thiol (0.19 g, 1.6 mmol) and
2-{4-(3-chloropropylthio)-3-methyl-2-pyridinyl!methyl!thio}-1H-benzimida
zole (0.36 g, 1.0 mmol) and 1.7 mmol of 1N sodium hydroxide solution. After
crystallization from ethyl acetate/diisopropyl ether, the title compound
is obtained as a colorless solid of melting point 98.degree.-99.degree. C.
(yield 58% of theory).
3.
2-{3-Methyl-4-(3-(1-methylimidazol-2-yl-thio)-propylthio)-2-pyridinyl!me
thyl!thio}-1H-benzimidazole
By the procedure described in Example 1, the title compound (68% of theory)
is obtained as a colorless solid of melting point 97.degree.-99.degree. C.
by reaction of 2-mercapto-1-methylimidazole with
2-{4-(3-chloropropylthio)-3-methyl-2-pyridinyl!methyl!thio}-1H-benzimida
zole and NaOH followed by crystallization from ethyl acetate/diisopropyl
ether.
4.
2-{4-3-(3-Amino-1,2,4-triazol-5-yl-thio)-propylthio!-3-methyl-2-pyridin
yl!methyl!thio}-1H-benzimidazole
By the procedure described in Example 1, the title compound (82% of theory)
is obtained as a colorless solid of melting point 94.degree.-96.degree. C.
by reaction of 3-amino-5-mercapto-1,2,4-triazole with
2-{4-(3-chloropropylthio)-3-methyl-2-pyridinyl!methyl!thio}-1H-benzimida
zole and NaOH.
5.
2-{4-3-(5-Amino-1,3,4-thiadiazol-2-yl-thio)-propylthio!-3-methyl-2-pyri
dinyl!methyl!thio}-1H-benzimidazole
By the procedure described in Example 1, the crude title compound is
obtained as a oil by reaction of 2-amino-5-mercapto-1,3,4-thiadiazole with
2-{4-(3-chloropropylthio)-3-methyl-2-pyridinyl!methyl!thio}-1H-benzimida
zole and NaOH. The title compound is obtained as the trihydrochloride by
dissolving in isopropanol, adding concentrated hydrochloric acid (about 5
equivalents), evaporating to dryness and triturating the residue with
acetone; colorless solid; 105.degree. C., evolution of gas; above
240.degree. C., decomposition.
6.
2-{4-3-Imidazol-2-yl-thio-propylthio!-3-methyl-2-pyridinyl!methyl!thio}
-1H-benzimidazole
By the procedure described in Example 1, the title compound (62% of theory)
is obtained by reaction of 2-mercaptoimidazole with
2-{4-(3-chloropropylthio)-3-methyl-2-pyridinyl!methyl!thio}-1H-benzimida
zole and NaOH followed by recrystallization from methanol/toluene;
colorless solid of melting point 195.degree. C. (decomposition).
7.
2-{3-Methyl-4-(3-(1,2,4-triazol-3-yl-thio)-propylthio)-2-pyridinyl!methy
l!thio}-1H-benzimidazole
By the procedure described in Example 1, the title compound (76% of theory)
is obtained by reaction of 3-mercapto-1,2,4-triazole with
2-{4-(3-chloropropylthio)-3-methyl-2-pyridinyl!methyl!thio}-1H-benzimida
zole and NaOH; colorless solid of melting point 80.degree.-82.degree. C.
8.
2-{3-Methyl-4-(3-(1-methyl-tetrazol-5-yl-thio)-propylthio)-2-pyridinyl!m
ethyl!thio}-1H-benzimidazole
By the procedure described in Example 1, the title compound (68% of theory)
is obtained by reaction of 1-methyl-5-mercaptotetrazole with
2-{4-(3-chloropropylthio)-3-methyl-2-pyridinyl!methyl!thio}-1H-benzimida
zole and NaOH; colorless solid of melting point 99.degree.-103.degree. C.
9.
2-{3-Methyl-4-(3-(thiazol-2-yl-thio)-propylthio)2-pyridinyl!methyl!thio}
-1H-benzimidazole
By the procedure described in Example 1, the title compound (63% of theory)
is obtained by reaction of 2-mercaptothiazole with
2-{4-(3-chloropropylthio)-3-methyl-2-pyridinyl!methyl!thio}-1H-benzimida
zole and NaOH; colorless solid of melting point 121.degree.-123.degree. C.
10.
2-{3-Methyl-4-(3-(pyridin-2-yl-thio)-propylthio)-2-pyridinyl!methyl!thio
}-1H-benzimidazole
By the procedure described in Example 1, the title compound (87% of theory)
is obtained by reaction of 2-mercaptopyridine with
2-{4-(3-chloropropylthio)-3-methyl-2-pyridinyl!methyl!thio}-1H-benzimida
zole and NaOH; colorless solid of melting point 97.degree.-99.degree. C.
11.
2-{3-Methyl-4-(3-(pyrimidin-2-yl-thio)-propylthio)-2-pyridinyl!methyl!th
io}-1H-benzimidazole
By the procedure described in Example 1, the title compound is obtained as
the monohydrate (92% of theory) by reaction of 2-mercaptopyrimidine with
2-{4-(3-chloropropylthio)-3-methyl-2-pyridinyl!methyl!thio}-1H-benzimida
zole and NaOH; colorless solid of melting point 118.degree.-119.degree. C.
12.
2-{4-(3-Benzimidazol-2-yl-thio)-propylthio-3-methyl-2-pyridinyl!methyl!
thio}-1H-benzimidazole
By the procedure described in Example 1, the title compound (62% of theory)
is obtained by reaction of 2-mercaptobenzimidazole with
2-{4-(3-chloropropylthio)-3-methyl-2-pyridinyl!methyl!thio}-1H-benzimida
zole and NaOH; colorless solid of melting point 177.degree.-180.degree. C.
(decomposition).
13.
2-{3-Methyl-4-(3-(phenylthio-propylthio)-2-pryridinyl!methyl!thio}-1H-be
nzimidazole
By the procedure described in Example 1, the title compound (95% of theory)
is obtained by reaction of thiophenol
2-{4-(3-chloropropylthio)-3-methyl-2-pyridinyl!methyl!thio}-1H-benzimida
zole and NaOH; colorless solid of melting point 141.degree.-143.degree. C.
14.
2-{3-Methyl-4-(3-(pyridine-1-oxo-2-yl-thio}-propylthio)-2-pyridinyl!meth
yl!thiol-1H-benzimidazole dihydrochloride
By the procedure described in Example 1, the title compound is obtained as
a viscous oil by reaction of 2-mercaptopyridine N-oxide with
2-{4-(3-chloropropylthio)-3-methyl-2-pyridinyl!methyl!thio}-1H-benzimida
zole and NaOH. The product is extracted with methylene chloride, the
extract is dried over potassium carbonate and evaporated to dryness, the
residue is dissolved in isopropanol, 3 equivalents of concentrated
hydrochloric acid are added and the mixture is heated to incipient
distillation. The solid which has precipitated out is filtered off and
dried in vacuo over KOH. The title compound (66% of theory) is obtained;
colorless solid of melting point 71.degree.-73.degree. C. (decomposition).
15.
2-{3-Methyl-4-(2-(pyridine-2-yl-thio)-ethylthio)-2-pyridinyl!methyl!thio
}-1H-benzimidazole
By the procedure described in Example 1, the title compound (72% of theory)
is obtained as a colorless solid of melting point 145.degree.-147.degree.
C. by reaction of 2-mercaptopyridine with
2-{4-(2-chloroethylthio)-3-methyl-2-pyridinyl!methyl!thio}-1H-benzimidaz
ole and sodium hydroxide solution followed by crystallization from
isopropanol.
16.
2-{3-Methyl-4-3-(4-methyl-pyrimidine-2-yl-thio)-propylthio!-2-pyridinyl
!methyl!thio}-1H-benzimidazole
By the procedure described in Example 1, the title compound is obtained by
reaction of 2-mercapto-4-methylpyrimidine; beige solid, melting point
70.degree.-72.degree. C.; yield 77% of theory.
17.
2-{4-3-(1-(2-Dimethylaminoethyl)-tetrazol-5-yl-thio)-propylthio)-3-meth
yl-2-pyridinyl!methyl!thio}-1H-benzimidazole trihydrochloride
By the procedure described in Examples 14 and 1, the title compound is
obtained by reaction with 1-(2-dimethylamino)-2-mercaptotetrazole; melting
point 131.degree.-133.degree. C., decomposition; yield 40% of theory.
18.
2-{3-Methyl-4-(3-(1,3,4-thiadiazol-2-yl-thio)-propylthio)-2-pyridinyl!me
thyl!thio}-1H-benzimidazole trihydrochloride
By the procedure described in Examples 14 and 1, the title compound is
obtained by reaction with 2-mercapto-1,3,4-thiadiazole; melting point
167.degree.-170.degree. C., decomposition; yield 53% of theory.
19.
2-{3-Methyl-4-(3-(pyridin-4-yl-thio)-propylthio)-2-pyridinyl!methyl!thio
}-1H-benzimidazole
By the procedure described in Example 1, the title compound is obtained by
reaction with 4-mercapto-pyridine; colorless powder; melting point:
164.degree.-166.degree. C.; yield 92% of theory.
20.
2-{3-Methoxy-4-(3-(1-methyl-tetrazol-5-yl-thio)-propylthio)-2-pyridinyl!
methyl!thio}-1H-benzimidazole dihydrochloride
By the procedure described in Examples 14 and 1, the title compound is
obtained as colorless crystals by reaction of
2-{4-(3-chloropropylthio)-3-methoxy-2-pyridinyl!methyl!thio}-1H-benzimid
azole with 1-methyl-5-mercaptotetrazole; melting point 135.degree. C.,
decomposition; yield 84% of theory.
21.
2-{3-Methoxy-4-(3-(pyrimidin-2-yl-thio)-propylthio)-2-pyridinyl!methyl!t
hio}-1H-benzimidazole
By the procedure described in Example 1, the title compound is obtained as
a beige powder by reaction of 2-mercaptopyrimidine with
2-{4-(3-chloropropylthio)-3-methoxy-2-pyridinyl!methyl!thio}-1H-benzimid
azole; melting point 88.degree.-90.degree. C., yield 77% of theory.
22. Sodium
5-(5-2-(1H-benzimidazol-2-yl-thiomethyl)-3-methyl-4-pyridinyl!-1,5-dithia
pent-1-yl}-tetrazole-1-acetate
By the procedure described in Example 1, the title compound is obtained by
reaction with 2-mercaptotetrazole-1-acetic acid and sodium hydroxide
solution followed by precipitation with acetone and recrystallization from
methanol/diisopropyl ether; beige powder; melting point from 180.degree.
C., decomposition; yield 34% of theory.
23.
2-{3-Methyl-4-(2-(1-methyl-tetrazol-5-yl-thio)-ethylthio)-2-pyridinyl!me
thyl!thio}-1H-benzimidazole
By the procedure described in Example 1, the title compound (82% of theory)
is obtained as a colorless solid by reaction of
1-methyl-5-mercaptotetrazole with
2-{4-(2-chloroethylthio)-3-methyl-2-pyridinyl!methyl!-thio)}-1H-benzimid
azole and NaOH. Melting point 204.degree.-208.degree. C.
24.
2-{3-Methyl-4-(4-(1-methyl-tetrazol-5-yl-thio)-butylthio)-2-pyridinyl!me
thyl!thio}-1H-benzimidazole
By the procedure described in Example 1, the title compound (48% of theory)
is obtained as a colorless solid by reaction of
1-methyl-5-mercaptotetrazole with
2-{4-(4-chlorobutylthio)-3-methyl-2-pyridinyl!methyl!thio}-1H-benzimidaz
ole and NaOH. Melting point 208.degree.-210.degree. C.
Starting Compounds
A1.
2-{4-(3-Chloropropylthio)-3-methyl-2-pyridinyl!methyl!thio}-1H-benzimida
zole
One equivalent of 2-chloromethyl-4-(3-chloropropylthio)-3-methylpyridine
hydrochloride (dissolved in 10 ml of water) is added dropwise to a
solution of 2-mercapto-1H-benzimidazole (1.5 g/10 mmol) in 40 ml of
ethanol and 21 ml of 1N sodium hydroxide solution at 40.degree. C. in the
course of 20 min. The mixture is then stirred at 50.degree.-60.degree. C.
for 2-3 hours and at room temperature for a further 3-4 hours, the ethanol
is distilled off on a rotary evaporator (1 kPa/40.degree. C.), the residue
is extracted 3 times with 20 ml of methylene chloride each time and the
extract is washed with 0.1N sodium hydroxide solution, dried over
potassium carbonate and evaporated to dryness in vacuo. For purification,
the crude product is chromatographed over silica gel (methylene chloride
20:1 to 3:1); the pure fractions collected are evaporated together in
vacuo and the residue is crystallized from methylene chloride/diisopropyl
ether. It is then recrystallized from methanol/toluene. Yield: 2.67 g
(74%) of the title compound as a colorless solid of melting point
112.degree.-114.degree. C.
A2. 2-Chloromethyl-4-(3-chloropropylthio)-3-methylpyridine hydrochloride
a) 2,3-Dimethyl-4-(3-hydroxypropylthio)pyridine N-oxide
6 g (60% pure) of NaOH are added in portions to 50 ml of dry
N-methylpyrrolidone (NMP), the mixture is stirred for 15 min, 9.5 g (0.11
mol) of 3-hydroxypropyl mercaptan are metered in over a period of 20 min.
and the mixture is stirred again for 30 min. until the evolution of gas
has ended. A solution of 14.4 g (0.1 mol) of 4-chloro-2,3-dimethylpyridine
N-oxide in 100 ml of NMP is then added dropwise in the course of 20 min.
and the reaction mixture is stirred at room temperature for 1 hour,
subsequently at 70.degree. C. for 1 hour and thereafter at 100.degree. C.
for a further hour.
When the reaction has been terminated, the mixture is allowed to cool and
is diluted with 500 ml of water and extracted 4 times with 300 ml of
methylene chloride each time. The combined organic phases are washed with
water, dried over magnesium sulfate and evaporated. The oily residue 10.0
g of crude 2,3-dimethyl-4-(3-hydroxypropylthio)-pyridine N-oxide! is
employed directly in the subsequent stage.
b) 2-Hydroxymethyl-4-(3-hydroxypropylthio)-3-methylpyridine
The yellow oil obtained under a) is dissolved in 100 ml of acetic anhydride
and the solution is stirred at 100.degree. C. for 2 hours. After
evaporation in vacuo, the brown oily residue is distilled in a bulb tube
distillation apparatus and reacted further without purification.
The oily distillate is heated at the reflux temperature in 100 ml of 2N
sodium hydroxide solution and 100 ml of isopropanol for 2 hours with
stirring, isopropanol is distilled off, the residue is extracted 3 times
with 100 ml of methylene chloride each time and the combined organic
phases are washed with water, dried over potassium carbonate and
concentrated in vacuo. 5.0 g of
2-hydroxymethyl-4-(3-hydroxypropylthio)-3-methylpyridine, which is reacted
further without purification, are obtained.
c) 2-Chloromethyl-4-(3-chloropropylthio)-3-methylpyridine Hydrochloride
5.0 g of the oil from Example b) are dissolved in methylene chloride (100
ml), 4 equivalents of thionyl chloride are added dropwise and the mixture
is stirred at room temperature for 20 hours. It is evaporated to dryness
and 4.5 g of the title compound are obtained as an oily residue which
gradually crystallizes and, if desired, can also be used as a solution in
ethanol directly for the reaction with optionally substituted
2-mercaptobenzimidazoles.
B1.
2-{4-(2-Chloroethylthio)-3-methyl-2-pyridinyl!-methyl!thio}-1H-benzimida
zole
By the procedure described in Example A1., the title compound (62% of
theory) is obtained as a colorless solid of melting point
178.degree.-180.degree. C. by reaction of 2-mercapto-1H-benzimidazole with
4-(2-chloroethylthio)-2-chloromethyl-3-methylpyridine hydrochloride and
NaOH followed by crystallization from ethyl acetate.
B2. 4-(2-Chloroethylthio)-2-chloromethyl-3-methylpyridine Hydrochloride
a) 2,3-Dimethyl-4-(2-hydroxyethylthio)pyridine N-oxide
By the procedure described in Example A2.a), the title compound is obtained
as an oily residue, which is employed in the subsequent stage without
further purification, by reaction of 4-chloro-2,3-dimethylpyridine N-oxide
with 2-mercaptoethanol and sodium hydride.
b) 4-(2-Hydroxyethylthio)-2-hydroxymethyl-3-methylpyridine
By the procedure described in Example A2.b), the title compound is obtained
as an oily residue, which is employed in the subsequent stage without
further purification, by reaction of the oil obtained under a) with acetic
anhydride and subsequent hydrolysis with NaOH.
c) 4-(2-Chloroethylthio)-2-chloromethyl-3-methylpyridine Hydrochloride
By the procedure described in Example A2.c), the title compound is obtained
as an oily residue, which is employed as a solution in ethanol directly
for the reaction with 2-mercaptobenzimidazole, by reaction of the oil
obtained under b) with thionyl chloride.
C1.
2-{4-(4-Chlorobutylthio)-3-methyl-2-pyridinyl!methyl!thio}-1H-benzimidaz
ole
By the procedure described in Example A1., the title compound (82% of
theory) is obtained as a pale yellow solid of melting point
151.degree.-153.degree. C. by reaction of 2-mercapto-1H-benzimidazole with
4-(4-chlorobutylthio)-2-chloromethyl-3-methylpyridine hydrochloride and
NaOH followed by crystallization from ethyl acetate/diisopropyl ether.
C2. 4-(4-Chlorobutylthio)-2-chloromethyl-3-methylpyridine Hydrochloride
a) 2,3-Dimethyl-4-(4-hydroxybutylthio)pyridine N-oxide
By the procedure described in Example A2.a), the title compound is obtained
as an oily residue, which is employed in the subsequent stage without
further purification, by reaction of 4-chloro-2,3-dimethylpyridine N-oxide
with 4-mercaptobutanol and sodium hydride.
b) 4-(4-Hydroxybutylthio)-2-hydroxymethyl-3-methylpyridine
By the procedure described in Example A2.b), the title compound is obtained
as an oily residue, which is employed in the subsequent stage without
further purification, by reaction of the oil obtained under a) with acetic
anhydride and subsequent hydrolysis with NaOH.
c) 4-(4-Chlorobutylthio)-2-chloromethyl-3-methylpyridine Hydrochloride
By the procedure described in Example A2.c), the title compound is obtained
as an oily residue, which is employed as a solution in ethanol directly
for the reaction with 2-mercaptobenzimidazole, by reaction of the oil
obtained under b) with thionyl chloride.
D1.
2-{4-(3-Chloropropylthio)-3-methoxy-2-pyridinyl!-methyl!thio}-1H-benzimi
dazole Dihydrochloride
2-Mercapto-1H-benzimidazole (10 g) and
2-chloromethyl-4-(3-chloropropylthio)-3-methoxypyridine hydrochloride (1
equivalent) are stirred in 150 ml of isopropanol and 15 ml of water at
80.degree. C. for 5 hours, the mixture is cooled and the solid which has
precipitated out is filtered off and recrystallized from
isopropanol/water. The title compound is obtained as a pale brown powder;
melting point 117.degree.-119.degree. C. (decomposition); yield: 67% of
theory.
D2. 2-Chloromethyl-4-(3-chloropropylthio)-3-methoxypyridine Hydrochloride
By the procedure described in Example A2 a, b, c, starting from
4-chloro-3-methoxy-2-methylpyridine N-oxide, the title compound is
obtained as an oil which slowly crystallizes and is further reacted
directly.
Commercial Utility
The excellent activity of compounds of the formula I and their salts
against Helicobacter bacteria enables them to be used in human medicine as
active compounds for the treatment of diseases caused by Helicobacter
bacteria.
The invention therefore furthermore relates to a method for treatment of
mammals, in particular humans, suffering from diseases caused by
Helicobacter bacteria. The method comprises administering a
therapeutically effective and pharmacologically tolerated amount of one or
more compounds of formula I and/or of their pharmacologically tolerated
salts to the sick individual.
The invention furthermore relates to compounds of formula I and their
pharmacologically tolerated salts for use in the treatment of diseases
caused by Helicobacter bacteria.
The invention also relates to the use of compounds of formula I and their
pharmacologically tolerated salts in the preparation of medicaments which
are employed for treatment of diseases caused by Helicobacter bacteria.
The invention furthermore relates to medicaments for combating Helicobacter
bacteria which comprise one or more compounds of formula I and/or their
pharmacologically tolerated salts.
Of the Helicobacter strains against which the compounds of the formula I
have proven active, the strain Helicobacter pylori may be mentioned in
particular.
The medicaments are prepared by methods which are known per se and are
familiar to the expert. As medicaments, the pharmacologically active
compounds of the formula I and their salts (=active compounds) are
employed either as such or, preferably, in combination with suitable
pharmaceutical auxiliaries, for example in the form of tablets, coated
tablets, capsules, emulsions, suspensions, gels or solutions, the active
compound content advantageously being between 0.1 and 95%.
The auxiliaries which are suitable for the desired medicament formulations
are familiar to the expert on the basis of his expert knowledge. In
addition to solvents, gel-forming agents, tableting auxiliaries and other
active compound excipients, it is possible to use, for example,
antioxidants, dispersing agents, emulsifiers, antifoams, flavor
correctants, preservatives, solubilizing agents, dyestuffs or permeation
promoters and complexing agents (for example cyclodextrins).
The active compounds can be administered, for example, parenterally (for
example intravenously) or, in particular, orally.
In human medicine, the active compounds are in general administered in a
daily dose of about 0.2 to 50, preferably 1 to 30 mg/kg of body weight, if
appropriate in the form of several, preferably 2 to 6, individual doses in
order to achieve the desired result.
In this connection, an aspect which is essential to the invention and
should be mentioned in particular is that the compounds of the formula I
in which n is the number 0 prove to be active against Helicobacter
bacteria even when the doses administered are below the doses which it
would be necessary to employ to achieve an inhibition of secretion of
gastric acid sufficient for therapeutic purposes.
Compounds of formula I in which n is the number 1 also have--in addition to
their activity against Helicobacter bacteria--a pronounced inhibiting
action on secretion of gastric acid. These compounds can accordingly also
be employed for the treatment of diseases caused by increased secretion of
gastric acid.
The compounds according to the invention can also be administered in fixed
or free combination together with a substance which neutralizes gastric
acid and/or inhibits secretion of gastric acid and/or with a substance
suitable for conventional control of Helicobacter pylori.
Examples which may be mentioned of substances which neutralize gastric acid
are sodium bicarbonate or other antacids (such as aluminum hydroxide,
magnesium aluminate or magaldrate). Examples which may be mentioned of
substances which inhibit secretion of gastric acid are H.sub.2 blockers
(for example cimetidine and ranitidine), H.sup.+ /K.sup.+ -ATPase
inhibitors (for example lansoprazol, omeprazol or, in particular,
pantoprazol), and so-called peripheral anticholinergics (for example
pirenzepine and telenzepine).
Substances which are suitable for conventional control of Helicobacter
pylori and which may be mentioned in particular are antimicrobially active
substances, such as, for example, penicillin G, gentamicin, erythromycin,
nitrofurazone, tinidazole, nitrofurantoin, furazolidone, metronidazole
and, in particular, amoxycillin, but also bismuth salts, such as, for
example, bismuth citrate.
Biological Studies
The compounds of formula I have been investigated in respect of their
activity against Helicobacter pylori in accordance with the method
described by Tomoyuki Iwahi et al. (Antimicrobial Agents and
Chemo-therapy, 1991, 490-496) using Columbia agar (Oxoid) over a growth
period of 4 days. The approximate MIC 50 values listed in the following
Table 2 resulted from these tests for the compounds studied (the numbers
stated for the compounds agree with the compound numbers in the
description).
TABLE 2
______________________________________
Compound Approx. MIC 50 value
No. (.mu.g/ml)
______________________________________
1 0.1
2 0.05
3 0.05
5 0.5
6 0.1
8 0.05
9 0.05
10 0.05
11 0.05
12 0.05
13 0.05
16 0.05
18 0.05
19 0.05
24 0.05
______________________________________
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